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1
Campbell, Grace Jean, Emma Langdale Hands, and Mathew Van de Pette. "The Role of CDKs and CDKIs in Murine Development." International Journal of Molecular Sciences 21, no. 15 (July 28, 2020): 5343. http://dx.doi.org/10.3390/ijms21155343.
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Cyclin-dependent kinases (CDKs) and their inhibitors (CDKIs) play pivotal roles in the regulation of the cell cycle. As a result of these functions, it may be extrapolated that they are essential for appropriate embryonic development. The twenty known mouse CDKs and eight CDKIs have been studied to varying degrees in the developing mouse, but only a handful of CDKs and a single CDKI have been shown to be absolutely required for murine embryonic development. What has become apparent, as more studies have shone light on these family members, is that in addition to their primary functional role in regulating the cell cycle, many of these genes are also controlling specific cell fates by directing differentiation in various tissues. Here we review the extensive mouse models that have been generated to study the functions of CDKs and CDKIs, and discuss their varying roles in murine embryonic development, with a particular focus on the brain, pancreas and fertility.
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Giannone, Gaia, Valentina Tuninetti, Eleonora Ghisoni, Sofia Genta, Giulia Scotto, Gloria Mittica, and Giorgio Valabrega. "Role of Cyclin-Dependent Kinase Inhibitors in Endometrial Cancer." International Journal of Molecular Sciences 20, no. 9 (May 12, 2019): 2353. http://dx.doi.org/10.3390/ijms20092353.
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Endometrial Cancer (EC) is an important cause of death in women worldwide. Despite early diagnosis and optimal treatment of localized disease, relapsed patients have few therapeutic options because after first line therapy, currently no standard of care exists. On the basis of endocrine positivity of most endometrioid ECs, Endocrine Therapy (ET) is a reasonable and widely accepted option. Better knowledge of molecular mechanisms involved in cancer highlighted the deregulated activity of Cyclin-Dependent Kinases (CDKs) in the cell cycle as a hallmark of carcinogenesis supporting the development of a new class of drugs: CDK inhibitors (CDKis). The aim of this review is to give an overview on CDKis preclinical, early clinical activity and future development in EC. Use of CDKis has a strong preclinical rationale but we have poor clinical data. Similar to breast cancer, most ongoing trials are investigating synergistic associations between CDKis and ET. These trials will probably help in defining the best clinical setting of CDKis in ECs, which are the best partner drugs, and how to manage CDKis toxicities with a focus on potential biomarkers of response.
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Phuong, Lisa, Janki Patel, Nadia Baka, Jessica Goldman, Michael Lyudmer, Stephanie Shamir, Junwen Deng, Alvaro Alvarez Soto, and Jesus Del Santo Anampa Mesias. "Effect of cyclin-dependent kinase 4 and 6 inhibitors (CDKIs) on body composition (BC) in patients (pts) with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (MBC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13033-e13033. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13033.
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e13033 Background: CDKIs with endocrine therapy (ET) is first-line treatment in HR+/HER2- MBC. Mouse models have shown that CDKIs prevent pRB phosphorylation in the mediobasal hypothalamus, a pathway hyper-activated in diet-induced obesity; and CDKIs lead to fat mass decrease without significant effect on lean mass. We aimed to assess the impact of CDKIs on weight (wt) and BC in pts with HR+/HER2- MBC. Methods: We identified pts with HR+/HER2- MBC who received CDKIs and ET from 2015-2018. To isolate the effect of CDKIs on BC, we identified another cohort of pts who only received ET. Body mass index (BMI), wt, and computed tomography (CT) records were reviewed. BC was analyzed at L3 on CT scans using Tomovision’s SliceOmatic v5.0 and included skeletal muscle area (SMA), skeletal muscle density (SMD), subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and muscle adiposity (MA). Total adipose tissue (TAT) was defined as SAT+VAT+MA. BC changes at 3 and 6 months of therapy were evaluated using paired t-tests. Results: There were 107 pts who received CDKI plus ET - 43% were Black, and 41% were Hispanic. CDKIs used were palbociclib (85%), abemaciclib (9%), and ribociclib (6%). ETs used were letrozole (47%), fulvestrant (39%), anastrozole (12%), and exemestane (2%). Median number of prior chemo and ET lines was 0 (range 0-5). 63 pts received ET alone. There was no difference in age (63 vs. 65 years, p = 0.26), BMI (28.80 vs. 28.12kg/m2, p = 0.48), and visceral disease (69% vs. 65%, p = 0.64) between CDKI plus ET and ET alone group. At month 3 of CDKI plus ET, there was a significant decrease in wt (-0.30kg, Interquartile range [IQR] -2.55-0.95, p = 0.02), BMI (-0.12kg/m2, IQR -1.06-0.46, p = 0.02), SAT (-8.05cm2, IQR -32.58-14.74, p = 0.01), and TAT (-8.51cm2, IQR -50.42-17.84, p < 0.01), with similar results at month 6. These findings were not seen in pts on ET only at 3 months (wt: 0.00kg, IQR -2.65-2.38, p = 0.98; BMI: 0.00kg/m2, IQR -1.07-0.91, p = 0.93; SAT: -2.97cm2, IQR -26.10-25.15, p = 0.60; TAT: -0.58cm2, IQR -44.39-27.43, p = 0.18), or at 6 months. There were no significant changes in VAT, SMA, SMD, or MA in both groups at 3 or 6 months. In the CDKI plus ET group, baseline wt (74.64 vs. 72.72kg, p = 0.60), BMI (29.21 vs. 27.88kg/m2, p = 0.31), and SAT (280.29 vs. 252.75cm2, p = 0.31) were not significantly different for those who did or did not develop grade 3/4 toxicities. We obtained similar results when stratifying toxicities into hematological- and GI-related events. Conclusions: CDKIs are associated with decrease in BMI and SAT with no significant effect on VAT, SMA, or SMD. Given the known effect of obesity on breast cancer prognosis, CDKIs may have an additional effect on breast cancer prognosis by modulating body fat. Further studies are required to determine if decrease in SAT is associated with breast cancer outcomes or toxicities in pts on CDKIs.
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Chao, Sheng-Hao, John R. Walker, Sumit K. Chanda, Nathanael S. Gray, and Jeremy S. Caldwell. "Identification of Homeodomain Proteins, PBX1 and PREP1, Involved in the Transcription of Murine Leukemia Virus." Molecular and Cellular Biology 23, no. 3 (February 1, 2003): 831–41. http://dx.doi.org/10.1128/mcb.23.3.831-841.2003.
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ABSTRACT Cyclin-dependent kinase inhibitors (CDKIs) have been shown to block human immunodeficiency virus and herpes simplex virus. It is hypothesized that CDKIs block viral replication by inhibiting transcription of specific cellular genes. Here we find that three CDKIs, flavopiridol, purvalanol A, and methoxy-roscovitine, block Moloney murine leukemia virus (MLV) transcription events. Using gene expression microarray technology to examine the inhibitory effects of CDKIs, we observed a cellular gene, the pre-B-cell leukemia transcription factor 1 (Pbx1) gene, down-regulated by CDKI treatment. The PBX consensus element (PCE), TGATTGAC, is conserved in the long terminal repeats of several murine retroviruses, including Moloney MLV. Mutations in the PCE completely inhibited viral transcription whereas overexpression of PBX1 and a PBX1-associated protein, PREP1, enhanced viral transcription. The interaction between the PCE and PBX1-PREP1 proteins was confirmed by gel shift experiments. Blocking PBX1 protein synthesis resulted in a significant decrease in viral transcription. Collectively, our results represent the first work demonstrating that the homeodomain proteins PBX1 and PREP1 are cellular factors involved in Moloney MLV transcription regulation.
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Dao, Mo A., and Catherine M. Verfaillie. "STI571 Suppresses Proliferation by Restoring Nuclear Cyclin Dependent Kinase Inhibitors (CDKIs) while STI571+TRAIL Promotes Cell Death by Decreasing Cytoplasmic CDKIs." Blood 104, no. 11 (November 16, 2004): 1992. http://dx.doi.org/10.1182/blood.v104.11.1992.1992.
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Abstract Cyclin dependent kinase inhibitors (CDKIs), p27Kip1 and p21Cip1, function as cell cycle inhibitors when located in the nucleus. When localized to the cytoplasm, these CDKIs can function as anti-apoptotic molecules by sequestering/preventing the activation of pro-apoptotic proteins such as ASK1 and procaspase-3. Our lab has reported elevated cytoplasmic CDKIs and decreased nuclear CDKIs in hematopoietic cells expressing BCR/ABL, the oncogene found in more than 90% of cases of chronic myeloid leukemia. Within the past decade, STI571 has been shown highly promising for CML treatment. However, there is increasing evidence suggesting that the drug might function more as a suppressor of proliferation and less as a promoter of cell death. In the current studies, we differentiate the effect of STI571 on proliferation vs. survival by tracking the subcellular increase/decrease in CDKIs using MO7e cells engineered to express BCR/ABL. To determine if a correlation exists between STI571 resistance and levels of cytoplasmic anti-apoptotic CDKIs, we also investigated changes in levels of nuclear vs. cytoplasmic CDKIs in LAMA84 -S (sensitive to STI571) vs. LAMA84-R (resistant to STI571). And lastly, we tested whether activation of TRAIL would enhance cell death in STI571-resistant cells. STI571 treatment increases nuclear CDKIs, correlating directly with a decrease in proliferation of MO7e/p210 cells. However, the high levels of cytoplasmic CDKIs in MO7e/p210bcr/abl was not modulated following STI571 treatment and cell death was not prominent, unless growth factors were removed. Moreover, cytoplasmic p21Cip co-immunoprecipitated with ASK1 and procaspase 3. When compared with LAMA-S cells, LAMA-R cells expressed even higher levels of cytoplasmic CDKIs. Treatment with STI571 decreased cytoplasmic CDKIs in LAMA84-S cells and resulted in cell death. As hypothesized, LAMA84-R cells did not show reduction in cytoplasmic CDKIs and did not enter apoptosis. However, when treated with STI571 and TRAIL, LAMA84-R cells showed a decrease in cytoplasmic CDKIs, and increase in apoptosis. Based on these observations, we conclude that: 1. BCR/ABL expression reduces nuclear CDKIs but increases cytoplasmic CDKIs. 2. STI571 treatment restores nuclear CDKIs and reduces cell proliferation of BCR/ABL expressing cells under physiological conditions. 3. Treatment of STI571+TRAIL reduces cytoplasmic CDKIs and increases cell death of BCR/ABL expressing cells, most notably, the STI571-resistant cells. In conclusion, we show that the imbalance between nuclear (cell cycle inhibitor) and cytoplasmic (cell survival enhancer) CDKIs exist in BCR/ABL-hematopoietic cells.
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Abdelmalak, Mary, Rajanbir Singh, Mohammed Anwer, Pavel Ivanchenko, Amritdeep Randhawa, Myra Ahmed, Anthony W. Ashton, Yanming Du, Xuanmao Jiao, and Richard Pestell. "The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance." Cancers 14, no. 21 (November 1, 2022): 5388. http://dx.doi.org/10.3390/cancers14215388.
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Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2−) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials.
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Gervaso, Lorenzo, Alberto J. Montero, Xuefei Jia, and Alok A. Khorana. "Venous thromboembolism in breast cancer patients receiving cyclin-dependent kinase inhibitors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18184-e18184. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18184.
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e18184 Background: Venous thromboembolism (VTE) complicates several anti-cancer regimens including chemotherapy and anti-angiogenic agents. Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are a new approach for hormone receptor positive (HR+) metastatic breast cancer (mBC). Reported VTE rates in randomized trials range from 0.6% for ribociclib (MONALEESA-2) to 2% for palbociclib (PALOMA-3) and 5% for abemaciclib (MONARCH-3) but these may underestimate actual rates compared to patients in clinical practice who are generally older and have greater comorbidities. Little is known about real world incidence or prevalence of VTE with CDKIs in mBC. The aim of this study was to evaluate rates of VTE in clinical practice and association with outcomes in mBC patients on CDKIs. Methods: We conducted a retrospective cohort study at Cleveland Clinic Taussig Cancer Institute, approved by the institutional review board. We identified consecutive mBC patients who received any of three FDA-approved CDKIs (palbociclib, ribociclib, abemaciclib) from 1/2015 through 12/2017. VTE including deep venous thrombosis (DVT) and pulmonary embolism (PE) were identified by electronic medical record review. Overall survival (OS), progression free survival (PFS) and time to VTE were estimated by the Kaplan-Meier method and evaluated for association with VTE using Cox proportional hazard regression. Results: The study population included 424 patients, with a median age at diagnosis of 54.76 yrs, (range 27 -85). Palbociclib was the most commonly used CDKI (n = 390, 91.8%); 27 patients (6.3%) received more than one drug. VTE during CDKI therapy occurred in 9% of patients (n = 38), including DVT in 52.6% (n = 20), PE in 18.5% (n = 7) and visceral vein thrombosis (VVT) in 15.8% (n = 6). Median time to VTE was 314 days, and 6-months rate was 4.1%. VTE was associated with numerically worse PFS and OS, but this was not statistically significant (PFS [HR 1.25, 95% CI 0.73 – 2.14, p = 0.42], OS [HR 1.60, 95% CI 0.89 – 2.87, p = 0.12]). Conclusions: VTE affected nearly 10% of breast cancer patients receiving CDKIs, 2- to 5-fold greater than reported in registration trials. Further work is necessary to identify pathophysiology, risk factors and benefit of thromboprophylaxis.
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Zeki, K., I. Morimoto, T. Arao, S. Eto, and U. Yamashita. "Interleukin-1alpha regulates G1 cell cycle progression and arrest in thyroid carcinoma cell lines NIM1 and NPA." Journal of Endocrinology 160, no. 1 (January 1, 1999): 67–73. http://dx.doi.org/10.1677/joe.0.1600067.
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This study provides the first report that the same cytokine (interleukin-1 (IL-1)) can induce opposite effects on cyclin-dependent kinases (Cdks) and Cdk inhibitors (Cdkis) in the G1 phase even in the same type of cancer cells (papillary thyroid carcinoma cells). Cell cycle analysis revealed an increase in NIM1 cells and a decrease in NPA cells in the S and G2+M phases after treatment with IL-1alpha. The addition of IL-1alpha to NIM1 cells reduced the expression of p16 and p21 protein and induced the expression of Cdk2 and Cdk4 protein, which leads to the phosphorylation of retinoblastoma protein. The addition of IL-1alpha to NPA cells induced the expression of p27 protein and reduced the expression of Cdk2 protein, which leads to induction of p107 protein expression. It is of interest that p21 protein expression was not observed in NPA cells. These results suggest that several Cdks and Cdkis play a regulatory role in the G1 cell cycle progression and arrest induced by IL-1alpha in thyroid carcinoma cell lines.
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Buckley, S., B. Driscoll, K. D. Anderson, and D. Warburton. "Cell cycle in alveolar epithelial type II cells: integration of Matrigel and KGF." American Journal of Physiology-Lung Cellular and Molecular Physiology 273, no. 3 (September 1, 1997): L572—L580. http://dx.doi.org/10.1152/ajplung.1997.273.3.l572.
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The regulation of cell cycle control in alveolar epithelial type II cells (AEC2) in response to peptide growth factors and extracellular matrix signals is not well understood. Herein, we have determined that, in adult rat AEC2 in primary culture on Engelbreth-Holm-Swarm biomatrix (Matrigel) in the presence of keratinocyte growth factor, the expression of key cell cycle control elements, including cyclins A and D and cyclin-dependent kinases (cdk) 1 and 4, is increased and that retinoblastoma protein (pRb) phosphorylation is also increased, with a corresponding decrease in the expression of p53 and the cdk inhibitors (cdkis) p21WAF1/CIP1 and p27KIP-1 compared with cells cultured on plastic. The Matrigel biomatrix-KGF culture conditions were also associated with an enhanced proliferative response, as measured by fluorescent-activated cell sorter analysis, thymidine incorporation into DNA, and proliferating cell nuclear antigen expression. This enhanced proliferation occurred with neither a soluble extract of Matrigel biomatrix nor with other simple biological matrices. We conclude that coordinated induction of key cyclins and cdks, with the concomitant suppression of key negative cell cycle regulators, occurs in AEC2 on Matrigel biomatrix in the presence of KGF. We speculate that the balance between cyclin and cdk activation and cdki suppression in AEC2 serves to integrate the combined influences of biomatrix and KGF signaling on pRb phosphorylation, thereby controlling transit through S phase of the cell cycle. Conversely, AEC2 express high levels of cdkis and p53 at rest in G1 phase. The latter finding may explain the quiescent state of normal adult AEC2 in vivo.
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Bencivenga, Debora, Emanuela Stampone, Angela Vastante, Myassar Barahmeh, Fulvio Della Ragione, and Adriana Borriello. "An Unanticipated Modulation of Cyclin-Dependent Kinase Inhibitors: The Role of Long Non-Coding RNAs." Cells 11, no. 8 (April 14, 2022): 1346. http://dx.doi.org/10.3390/cells11081346.
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It is now definitively established that a large part of the human genome is transcribed. However, only a scarce percentage of the transcriptome (about 1.2%) consists of RNAs that are translated into proteins, while the large majority of transcripts include a variety of RNA families with different dimensions and functions. Within this heterogeneous RNA world, a significant fraction consists of sequences with a length of more than 200 bases that form the so-called long non-coding RNA family. The functions of long non-coding RNAs range from the regulation of gene transcription to the changes in DNA topology and nucleosome modification and structural organization, to paraspeckle formation and cellular organelles maturation. This review is focused on the role of long non-coding RNAs as regulators of cyclin-dependent kinase inhibitors’ (CDKIs) levels and activities. Cyclin-dependent kinases are enzymes necessary for the tuned progression of the cell division cycle. The control of their activity takes place at various levels. Among these, interaction with CDKIs is a vital mechanism. Through CDKI modulation, long non-coding RNAs implement control over cellular physiology and are associated with numerous pathologies. However, although there are robust data in the literature, the role of long non-coding RNAs in the modulation of CDKIs appears to still be underestimated, as well as their importance in cell proliferation control.
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Mason, Jeremy, Yutao Gong, Laleh Amiri-Kordestani, Suparna Wedam, Jennifer J. Gao, Tatiana M. Prowell, Harpreet Singh, et al. "Model Development of CDK4/6 Predicted Efficacy in Patients With Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Advanced or Metastatic Breast Cancer." JCO Clinical Cancer Informatics, no. 5 (June 2021): 758–67. http://dx.doi.org/10.1200/cci.21.00025.
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PURPOSE Three cyclin-dependent kinase 4/6 inhibitors (CDKIs) are approved by the US Food and Drug Administration for the treatment of patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative advanced or metastatic breast cancer in combination with hormonal therapy (HT). We hypothesized that on an individual basis, efficacy outcomes and adverse event (AE) development can be predicted using baseline patient and tumor characteristics. METHODS Individual-level data from seven randomized controlled trials submitted to the US Food and Drug Administration for new or supplemental marketing applications of CDKIs were pooled. Progression-free survival (PFS), overall survival (OS), and AE prediction models were developed for specific treatment regimens (HT v HT plus CDKI). An individual's characteristics were used in all models simultaneously to create a group of predicted outcomes that are comparable across treatment settings. RESULTS Accuracy of the PFS and OS prediction models for HT were 66% and 64%, respectively, with the strongest predictors being menopausal status and therapy line. The corresponding AE prediction models resulted in an average area under the curve of 0.613. Accuracy of the PFS and OS prediction models for HT plus CDKI were 62% and 63%, respectively, with the strongest predictors being histologic grade for both. The corresponding AE prediction models resulted in an average area under the curve of 0.639. CONCLUSION This exploratory analysis demonstrated that models of efficacy outcomes and AE development can be developed using baseline patient and tumor characteristics. Comparison of paired models can inform treatment selection for individuals on the basis of the patient's personalized goals and concerns. Although use of CDKIs is standard of care in the first- or second-line setting, this model provides prognostic information that may inform individual treatment decisions.
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Matushansky, Igor, Farshid Radparvar, and Arthur I. Skoultchi. "Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors." Blood 96, no. 8 (October 15, 2000): 2755–64. http://dx.doi.org/10.1182/blood.v96.8.2755.
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Abstract Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.
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Matushansky, Igor, Farshid Radparvar, and Arthur I. Skoultchi. "Manipulating the onset of cell cycle withdrawal in differentiated erythroid cells with cyclin-dependent kinases and inhibitors." Blood 96, no. 8 (October 15, 2000): 2755–64. http://dx.doi.org/10.1182/blood.v96.8.2755.h8002755_2755_2764.
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Terminal differentiation of erythroid cells results in terminal cell divisions followed by irreversible cell cycle withdrawal of hemoglobinized cells. The mechanisms leading to cell cycle withdrawal were assessed in stable transfectants of murine erythroleukemia cells, in which the activities of cyclin-dependent kinases (CDKs) and CDK inhibitors (CDKIs) could be tightly regulated during differentiation. Cell cycle withdrawal of differentiating cells is mediated by induction of several CDKIs, thereby leading to inhibition of CDK2 and CDK4. Manipulation of CDK activity in differentiating cells demonstrates that the onset of cell cycle withdrawal can be either greatly accelerated or greatly delayed without affecting hemoglobin levels. Extending the proliferation of differentiating cells requires the synergistic action of CDK2 and CDK4. Importantly, CDK6 cannot substitute for CDK4 in this role, which demonstrates that the 2 cyclin D–dependent kinases are functionally different. The results show that differentiating hemoglobinized cells can be made to proliferate far beyond their normal capacity to divide.
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Schwartz, Gary K., and Manish A. Shah. "Targeting the Cell Cycle: A New Approach to Cancer Therapy." Journal of Clinical Oncology 23, no. 36 (December 20, 2005): 9408–21. http://dx.doi.org/10.1200/jco.2005.01.5594.
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The cell cycle represents a series of tightly integrated events that allow the cell to grow and proliferate. Critical parts of the cell cycle machinery are the cyclin-dependent kinases (CDKs), which, when activated, provide a means for the cell to move from one phase of the cell cycle to the next. The CDKs are regulated positively by cyclins and regulated negatively by naturally occurring CDK inhibitors (CDKIs). Cancer represents a dysregulation of the cell cycle such that cells that overexpress cyclins or do not express the CDKIs continue to undergo unregulated cell growth. The cell cycle also serves to protect the cell from DNA damage. Thus, cell cycle arrest, in fact, represents a survival mechanism that provides the tumor cell the opportunity to repair its own damaged DNA. Thus, abrogation of cell cycle checkpoints, before DNA repair is complete, can activate the apoptotic cascade, leading to cell death. Now in clinical trials are a series of targeted agents that directly inhibit the CDKs, inhibit unrestricted cell growth, and induce growth arrest. Recent attention has also focused on these drugs as inhibitors of transcription. In addition, there are now agents that abrogate the cell cycle checkpoints at critical time points that make the tumor cell susceptible to apoptosis. An understanding of the cell cycle is critical to understanding how best to clinically develop these agents, both as single agents and in combination with chemotherapy.
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DeSouza, Karen, Daniel Yeo, Maria Diossy, Sumbal Umar, Emma Gore, Sachin Trivedi, Anjana Anand, Srinivasan Madhusudan, and Sarah Khan. "Real-world outcomes from the systemic use of CDK 4/6 inhibitors (CDKIs) in the management of ER positive (+) HER2 negative (-) metastatic breast cancer (mBC)." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e13031-e13031. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e13031.
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e13031 Background: The use of CDKIs have transformed the management of ER+HER2- mBC. As the real-world data matures, this project describes patterns in response to systemic therapy that may inform treatment planning and prognostication. Methods: We analysed the ER+HER2- mBC dataset at Nottingham University Hospitals NHS Trust (NUH) generated by reviewing clinical notes, radiology and e-prescribing records to collect clinical data on patients treated with CDKIs between 01/10/2016 - 01/10/2020. Results: 272 patients with a median age of 65 years (30-90 years) were treated with CDKIs (palbociclib 54.0% (n=147); ribociclib 19.5% (n=53); abemaciclib 26.5% (n=72)) in combination with endocrine therapies (letrozole, anastrozole, exemestane and, fulvestrant). Median overall survival was 49.5 months. Treatment with first-line CDKIs (69.8%; n=190) resulted in superior PFS when compared to CDKIs in a ≥ second-line setting (30.2%; n=82) i.e., mPFS 21.3 vs 12.2 months (HR 0.67; 95% CI, 0.47-0.96; P=0.02). Univariate analysis shown in the table below indicates the benefit to PFS from presentations with de novo mBC and the absence of visceral metastases. In patients treated curatively for early breast cancer (EBC), better outcomes were demonstrated in patients presenting with mBC, >12 months versus ≤12 months of completion of adjuvant endocrine therapy i.e., mPFS 28.4 vs 12.1 months (HR 0.50; 95% CI, 0.30-0.84; P=0.004) when treated with first-line CDKIs. A multivariate analysis identified benefit to PFS from first-line therapy with CDKIs (HR 0.70; 95% CI, 0.49-1.01; P=0.05) and presentation with de novo mBC (HR 0.56; 95% CI, 0.37-0.85; P=0.006). The presence of visceral metastases was associated with poorer outcomes (HR 1.52; 95% CI, 1.08-2.15; P=0.01). Conclusions: This analysis confirms the PFS benefit from CDKIs demonstrated in clinical trials is mirrored in the real-world setting. The analysis was not powered to delineate survival benefit between the individual CDKIs. Presentations with mBC following a prior history of EBC, within ≤12 months of completion of adjuvant endocrine therapy, and with visceral metastases may help predict poorer clinical outcomes and may need to be considered when prognosticating and in treatment planning. This analysis is hypotheses-generating and we will confirm our findings in a prospective manner as the dataset is expanded.[Table: see text]
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Richter, Anna, Nina Schoenwaelder, Sina Sender, Christian Junghanss, and Claudia Maletzki. "Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches." Cancers 13, no. 10 (May 20, 2021): 2497. http://dx.doi.org/10.3390/cancers13102497.
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Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions.
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Gao, Jennifer J., Joyce Cheng, Tatiana Michelle Prowell, Erik Bloomquist, Shenghui Tang, Suparna B. Wedam, Melanie E. Royce, et al. "Overall survival in patients with breast cancer treated with a CDK 4/6 inhibitor plus fulvestrant: A U.S. Food and Drug Administration pooled analysis." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 1055. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.1055.
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1055 JJG, JC, TMP contributed equally. JAB, LAK contributed equally. Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first or secondline treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival of patients in certain clinicopathologic subgroups, and results showed a consistent benefit from the addition of a CDKI to endocrine therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI plus fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of a CDKI plus fulvestrant submitted to the FDA in support of marketing applications. All analyzed patients received at least one dose of a CDKI or placebo, plus fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Results: Results of OS analyses, including all pooled patients, patients treated in the first-line setting, and patients treated in the second line and later settings, are summarized in the table below. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding a CDKI to fulvestrant. In patients age < 40, the estimated OS HR favored fulvestrant alone, but this subgroup had a small sample size (n=89), so this result must be interpreted with caution. All results are considered exploratory and hypothesis-generating. Conclusions: Addition of CDKIs to fulvestrant appears to confer a consistent survival benefit across all pooled patients and within most clinicopathological subgroups of interest.[Table: see text]
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Croucher, David R., Danny Rickwood, Carole M. Tactacan, Elizabeth A. Musgrove, and Roger J. Daly. "Cortactin Modulates RhoA Activation and Expression of Cip/Kip Cyclin-Dependent Kinase Inhibitors To Promote Cell Cycle Progression in 11q13-Amplified Head and Neck Squamous Cell Carcinoma Cells." Molecular and Cellular Biology 30, no. 21 (August 30, 2010): 5057–70. http://dx.doi.org/10.1128/mcb.00249-10.
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ABSTRACT The cortactin oncoprotein is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC), often due to amplification of the encoding gene (CTTN). While cortactin overexpression enhances invasive potential, recent research indicates that it also promotes cell proliferation, but how cortactin regulates the cell cycle machinery is unclear. In this article we report that stable short hairpin RNA-mediated cortactin knockdown in the 11q13-amplified cell line FaDu led to increased expression of the Cip/Kip cyclin-dependent kinase inhibitors (CDKIs) p21WAF1/Cip1, p27Kip1, and p57Kip2 and inhibition of S-phase entry. These effects were associated with increased binding of p21WAF1/Cip1 and p27Kip1 to cyclin D1- and E1-containing complexes and decreased retinoblastoma protein phosphorylation. Cortactin regulated expression of p21WAF1/Cip1 and p27Kip1 at the transcriptional and posttranscriptional levels, respectively. The direct roles of p21WAF1/Cip1, p27Kip1, and p57Kip2 downstream of cortactin were confirmed by the transient knockdown of each CDKI by specific small interfering RNAs, which led to partial rescue of cell cycle progression. Interestingly, FaDu cells with reduced cortactin levels also exhibited a significant diminution in RhoA expression and activity, together with decreased expression of Skp2, a critical component of the SCF ubiquitin ligase that targets p27Kip1 and p57Kip2 for degradation. Transient knockdown of RhoA in FaDu cells decreased expression of Skp2, enhanced the level of Cip/Kip CDKIs, and attenuated S-phase entry. These findings identify a novel mechanism for regulation of proliferation in 11q13-amplified HNSCC cells, in which overexpressed cortactin acts via RhoA to decrease expression of Cip/Kip CDKIs, and highlight Skp2 as a downstream effector for RhoA in this process.
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Khosravi, Mohammad Reza, Mohammad Hossein Mohammadi, Parinaz Khadem, Sahar Lashkari, Hamideh Aghaeenezhad, Ahmad Gharehbaghian, Zaher Khazaei, and Mehdi Allahbakhshian Farsani. "Evaluation of P21Cip1 and P27Kip1 expression in de novo acute lymphoblastic leukemia patients." Biomedical Research and Therapy 5, no. 7 (July 28, 2018): 2518–27. http://dx.doi.org/10.15419/bmrat.v5i7.461.
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Background: Acute lymphoblastic leukemia (ALL) arises from an imbalanced proliferation and differentiation of lymphoid progenitors due to special chromosomal and epigenetic abnormalities affecting cell cycle regulation. The cyclin-dependent kinase inhibitor (CDKI) family has crucial functions in G1 progression and G1 to S entry regulation. Among CDKIs, P21 and P27 are able to exert remarkable effects on all CDKs. Hence, we investigated the expression levels of P21 and P27 in ALL patients to determine whether or not their expression had been altered.
Materials and Methods: In the present study, we evaluated P21 and P27 expression in bone marrow and peripheral blood samples of 52 newly diagnosed ALL patients (30 males, 22 females) and 13 healthy normal controls (5 males, 8 females) using quantitative real-time PCR. Data were analyzed via SPSS (version 16) software and P<0.05 was assigned as the statistical significance level.
Results: Our findings demonstrated lower expression levels of P21 and P27 in ALL patients compared with normal controls (8.33- and 1.69-fold change, respectively). P21 and P27 expression was significantly different between T-cell acute lymphoblastic leukemia (T-ALL) and B-cell acute lymphoblastic leukemia (B-ALL) patients (P= 0.03).
Conclusion: Since P21 and P27 are able to influence the activity of both cyclins and CDKs, it is postulated that decreased expression of these genes reduces P21- and P27- mediated suppressive effects on cyclins and CDKs. Therefore, these events facilitate the activation of cyclins and CDKs which may result in cancer progression in ALL patients.
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Roncato, Rossana, Jacopo Angelini, Arianna Pani, Erika Cecchin, Andrea Sartore-Bianchi, Salvatore Siena, Elena De Mattia, Francesco Scaglione, and Giuseppe Toffoli. "CDK4/6 Inhibitors in Breast Cancer Treatment: Potential Interactions with Drug, Gene, and Pathophysiological Conditions." International Journal of Molecular Sciences 21, no. 17 (September 1, 2020): 6350. http://dx.doi.org/10.3390/ijms21176350.
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Palbociclib, ribociclib, and abemaciclib belong to the third generation of cyclin-dependent kinases inhibitors (CDKis), an established therapeutic class for advanced and metastatic breast cancer. Interindividual variability in the therapeutic response of CDKis has been reported and some individuals may experience increased and unexpected toxicity. This narrative review aims at identifying the factors potentially concurring at this variability for driving the most appropriate and tailored use of CDKis in the clinic. Specifically, concomitant medications, pharmacogenetic profile, and pathophysiological conditions could influence absorption, distribution, metabolism, and elimination pharmacokinetics. A personalized therapeutic approach taking into consideration all factors potentially contributing to an altered pharmacokinetic/pharmacodynamic profile could better drive safe and effective clinical use.
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Adona, Paulo Roberto, and Cláudia Lima Verde Leal. "Meiotic inhibition with different cyclin-dependent kinase inhibitors in bovine oocytes and its effects on maturation and embryo development." Zygote 12, no. 3 (August 2004): 197–204. http://dx.doi.org/10.1017/s0967199404002771.
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Cyclin-dependent kinase inhibitors (CDKIs) such as butyrolactone I (BL-I) and roscovitine (ROS) maintain bovine oocytes blocked at the germinal vesicle (GV) stage. Bohemine (BOH), another CDKI, has been used for oocyte activation. The objective of this study was to determine whether BOH blocks meiosis and to compare its efficiency with other CDKIs (ROS and BL-I). Oocytes were cultured for 24 h in 0, 50, 100 and 150 μM BOH to determine the best concentration for blocking meiosis (experiment 1). GV rates were 3.3%, 64.5%, 83.3% and 88.9% (0, 50, 100 and 150 μM, respectively). Experiment 2 compared meiotic inhibition efficiency of BOH (100 μM), ROS (25 μM) and BL-I (100 μM). BL-I presented the highest GV rates (97.5%). BOH and ROS were similar to each other (85.4% and 79.9%, respectively). To assess the reversibility of meiotic inhibition (experiment 3), oocytes underwent in vitro maturation (IVM) for 18 h after the 24 h inhibition. Control oocytes were submitted to IVM for 18 h (C18) or 24 h (C24). Maturation rates were either similar to (ROS and BL-I: 96.0% and 93.6%, respectively) or superior to (BOH, 96.9%) C24 (91.0%). All groups were superior to C18 (82.5%). In experiment 4, oocytes were treated as in experiment 3 and then in vitro fertilized and cultured for 8 days. Blastocyst rates for BL-I (32.3%) were similar to C24 (35.0%), while those for BOH (20.2%) and ROS (24.2%) were inferior. All groups were inferior to C18 (43.4%). The results show that: (a) BOH inhibits meiosis resumption; (b) BL-I is the most effective of the CDKIs tested for blocking meiosis; (c) culture of oocytes with meiosis inhibitors is fully reversible in terms of nuclear maturation but they may either decrease (BOH and ROS) or maintain (BL-I) embryo development rates.
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Riess, Christin, Katharina del Moral, Adina Fiebig, Philipp Kaps, Charlotte Linke, Burkhard Hinz, Anne Rupprecht, et al. "HGG-13. Combined CDK inhibition and arginine-deprivation as targeted therapy for arginine-auxotrophic glioblastoma multiforme cells." Neuro-Oncology 24, Supplement_1 (June 1, 2022): i62—i63. http://dx.doi.org/10.1093/neuonc/noac079.228.
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Abstract INTRODUCTION/BACKGROUND: Glioblastoma multiforme show constitutive activation of cyclin-dependent kinases (CDKs) or arginine auxotrophy. This renders tumor cells vulnerable towards arginine-depleting substances, such as arginine deiminase from Streptococcus pyogenes (SpyADI). Previously, we confirmed the susceptibility of patient-derived GBM cells towards administration of SpyADI as well as CDK inhibitors (CDKis). To improve effects, we applied a sequential (SEQ) CDKi/SpyADI approach to examine mechanistic insights and drug susceptibility. MATERIALS AND METHODS: Three arginine-auxotrophic patient-derived GBM lines with different molecular characteristics were cultured in 2D and 3D (spheres and glioma stem-like cells (GSC)) and effects of this combined CDKi/SpyADI approach were analyzed. This included viability staining via Calcein AM in 2D and 3D-Glo in 3D culture and cell death analysis via flow cytometry. Therapy-induced morphological changes were identified with transmission electron microscopy (TEM). Besides, 3D-invasiveness, cellular stress, and DNA damage responses were measured. RESULTS: All SEQ-CDKi/SpyADI combinations yielded synergistic antitumoral effects, characterized by impaired cell proliferation, invasiveness, and viability. Notably, this SEQ-CDKi/SpyADI approach was most effective in 3D models. Mitochondrial impairment was demonstrated by increasing mitochondrial membrane potential and decreasing oxygen consumption rate along with extracellular acidification rate after abemaciclib/SpyADI monotherapy or its combination regimens. TEM confirmed damaged mitochondria and endoplasmic reticulum together with increased vacuolization under CDKi mono- and SEQ- CDKi/SpyADI combination therapy. SEQ-abemaciclib/SpyADI treatment suppressed the DSB repair system via NHEJ and HR, whereas SEQ-dinaciclib/SpyADI treatment increased γ-H2AX accumulation and induced Rad51/Ku80. The latter combination also activated the stress sensor GADD45 and β-catenin antagonist AXIN2. CONCLUSION: This study highlights the antitumoral potential of a combined SpyADI/CDKi approach. We show that sequential application of these substances has complex effects on mitochondrial dysfunction, invasiveness, and DNA-damage response. This provides a good starting point for further proof-of-concept studies to move forward with this strategy.
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Mou, Jiajia, Danghui Chen, and Yanru Deng. "Inhibitors of Cyclin-Dependent Kinase 1/2 for Anticancer Treatment." Medicinal Chemistry 16, no. 3 (April 17, 2020): 307–25. http://dx.doi.org/10.2174/1573406415666190626113900.
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Background: The cell cycle is regulated by cyclin-dependent kinases (CDKs) and their cognate cyclins, along with their endogenous inhibitors (CDKIs). CDKs act as central regulators in this process. Different CDKs play relevant roles in different phases. Among all CDKs, CDK1 is indispensible, which can drive all events that are required in the cell cycle in the absence of interphase CDKs (CDK2, CDK3, CDK4 and CDK6). So, CDK1 is an attractive target for anticancer drug development. Methods: CDK1 and CDK2 have 89.19% similar residues and 74.32% identical residues, their structures especially the ATP-binding sites are of great similarity. So, it is difficult to inhibit CDK1 and CDK2 individually. In this review, recent advances about CDK1/2 inhibitors were summarized. The chemical structures of different classes of CDK1/2 inhibitors and their structure activity are presented. Results: 19 kinds of CDK1/2 or CDK1 inhibitors with different scaffolds, including CDK2 allosteric inhibitors, were summarized. Some inhibitors are nature derived, for example, phenanthrene derivatives, nortopsentin derivatives, variolin B derivatives and meridians. Conclusion: Nature products, especially marine ones are potential resources for CDK1 inhibitors development. The findings of CDK2 allosteric inhibitors open an avenue to the discovery of novel selective CDK1 or other CDKs allosteric inhibitors.
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Jerez, Jose Manuel, Nuria Ribelles, Pablo Rodriguez-Brazzarola, Tamara Diaz Redondo, Begoña Jimenez Rodriguez, Alfonso Sanchez-Muñoz, Antonia Marquez, et al. "Prediction of early progression (EP) to CDKIs first line treatment in ER+/HER2- metastatic breast cancer (MBC) using machine learning." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13040-e13040. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13040.
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e13040 Background: The treatment of luminal MBC has undergone a substantial change with the use of cyclin dependent kinase 4/6 inhibitors (CDKIs). Nevertheless, there is not a clearly defined subgroup of patients who do not initially respond to CDKIs and show EP. Methods: MBC ER+/HER2- patients who have received at least one line of treatment were eligible. The event of interest was disease progression within 6 months of first line treatment according to the type of therapy administered. The first line treatments were categorized in chemotherapy (CT), hormonal therapy (HT), CT plus maintenance HT and HT plus CDKIs. Free text data from clinical visits registered in our Electronic Health Record were obtained until the date of first treatment in order to generate a feature vector composed of the word frequencies for each visit of every patient. Six different machine learning algorithms were evaluated to predict the event of interest and to obtain the risk of EP for every type of therapy. Area under the ROC curve (AUC), True Positive Rate (TPR) and True Negative Rate (TNR) were assessed using 10-fold cross validation. Results: 610 RE+/HER2- MBC treated between November 1991 and August 2019 were included. Median follow up for metastatic disease was 28 months. 17426 clinical visits were analyzed (per patient: range 1-173; median 30). 119 patients received CT as first line treatment, 311 HT, 117 CT plus maintenance HT and 63 HT plus CDKIs. There were 379 patients with disease progression, from which 126 were within 6 months from first line treatment (54 events with CT, 57 with HT, 4 with CT plus maintenance HT and 11 with HT plus CDKIs). The model that yields the best results was the GLMBoost algorithm: AUC 0.72 (95%CI 0.67-0.77), TPR 70.85% (95%CI 70.63%-71.06%), TNR 66.27% (95% 66.08%-66.46%). Conclusions: Our model based on unstructured data from real-world patients predicts EP and establishes the risk for each of the different types of treatment for MBC ER+/HER2-. Obviously an additional validation is needed, but a tool with these characteristics could help to select the best available treatment when that decision has to be made, avoiding those therapies that are probably not to be effective.
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Han, Xu, Yijin Kuang, Huiyong Chen, Ting Liu, Ji Zhang, and Jing Liu. "p19INK4d: More than Just a Cyclin-Dependent Kinase Inhibitor." Current Drug Targets 21, no. 1 (December 20, 2019): 96–102. http://dx.doi.org/10.2174/1389450120666190809161901.
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Cyclin-dependent kinase inhibitors (CDKIs) are important cell cycle regulators. The CDKI family is composed of the INK4 family and the CIP/KIP family. p19INK4d belongs to the INK4 gene family and is involved in a series of normal physiological activities and the pathogenesis of diseases. Many factors play regulatory roles in the p19INK4d gene expression at the transcriptional and posttranscriptional levels. p19INK4d not only regulates the cell cycle but also plays regulatory roles in apoptosis, DNA damage repair, cell differentiation of hematopoietic cells, and cellular senescence. In this review, the regulatory network of the p19INK4d gene expression and its biological functions are summarized, which provides a basis for further study of p19INK4d as a drug target for disease treatment.
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Bryant, Patrick, Qingxia Zheng, and Kevin Pumiglia. "Focal Adhesion Kinase Controls Cellular Levels of p27/Kip1 and p21/Cip1 through Skp2-Dependent and -Independent Mechanisms." Molecular and Cellular Biology 26, no. 11 (June 1, 2006): 4201–13. http://dx.doi.org/10.1128/mcb.01612-05.
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ABSTRACT Endothelial cell proliferation is a critical step in angiogenesis and requires a coordinated response to soluble growth factors and the extracellular matrix. As focal adhesion kinase (FAK) integrates signals from both adhesion events and growth factor stimulation, we investigated its role in endothelial cell proliferation. Expression of a dominant-negative FAK protein, FAK-related nonkinase (FRNK), impaired phosphorylation of FAK and blocked DNA synthesis in response to multiple angiogenic stimuli. These results coincided with elevated cyclin-dependent kinase inhibitors (CDKIs) p21/Cip and p27/Kip, as a consequence of impaired degradation. FRNK inhibited the expression of Skp2, an F-box protein that targets CDKIs, by inhibiting mitogen-induced mRNA. The FAK-regulated degradation of p27/Kip was Skp2 dependent, while levels of p21/Cip were regulated independent of Skp2. Skp2 is required for endothelial cell proliferation as a consequence of degrading p27. Finally, knockdown of both p21 and p27 in FRNK-expressing cells completely restored mitogen-induced endothelial cell proliferation. These data demonstrate a critical role for FAK in the regulation of CDKIs through two independent mechanisms: Skp2 dependent and Skp2 independent. They also provide important insights into the requirement of focal adhesion kinase for normal vascular development and reveal novel regulatory control points for angiogenesis.
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Cheng, Qiong, Zhikun Ma, Yujie Shi, Amanda B. Parris, Lingfei Kong, and Xiaohe Yang. "FGFR1 Overexpression Induces Cancer Cell Stemness and Enhanced Akt/Erk-ER Signaling to Promote Palbociclib Resistance in Luminal A Breast Cancer Cells." Cells 10, no. 11 (November 4, 2021): 3008. http://dx.doi.org/10.3390/cells10113008.
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Resistance to CDK4/6 inhibitors (CDKis) is emerging as a clinical challenge. Identification of the factors contributing to CDKi resistance, with mechanistic insight, is of pivotal significance. Recent studies linked aberrant FGFR signaling to CDKi resistance. However, detailed mechanisms are less clear. Based on control and FGFR1 overexpressing luminal A cell line models, we demonstrated that FGFR1 overexpression rendered the cells resistant to palbociclib. FGFR1 overexpression abolished palbociclib-mediated cell cycle arrest, as well as the attenuated palbociclib-induced inhibition of G1/S transition regulators (pRb, E2F1, and cyclin D3) and factors that promote G2/M transition (cyclin B1, cdc2/CDK1, and cdc25). Importantly, FGFR1-induced palbociclib resistance was associated with promotion of cancer cell stemness and the upregulation of Wnt/β-catenin signaling. We found that palbociclib may function as an ER agonist in MCF-7/FGFR1 cells. Upregulation of the ER-mediated transcription in MCF-7/FGFR1 cells was associated with ERα phosphorylation and enhanced receptor tyrosine kinase signaling. The combination of palbociclib with FGFR-targeting AZD4547 resulted in remarkable synergistic effects on MCF-7/FGFR1 cells, especially for the inhibition of cancer cell stemness. Our findings of FGFR1-induced palbociclib resistance, promotion of cancer stem cells and associated molecular changes advance our mechanistic understanding of CDKi resistance, which will facilitate the development of strategies targeting CDKi resistance in breast cancer treatment.
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Bonelli, Patrizia, Franca Maria Tuccillo, Antonella Borrelli, Antonietta Schiattarella, and Franco Maria Buonaguro. "CDK/CCN and CDKI Alterations for Cancer Prognosis and Therapeutic Predictivity." BioMed Research International 2014 (2014): 1–15. http://dx.doi.org/10.1155/2014/361020.
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The regulation of cell growth and division occurs in an accurate sequential manner. It is dictated by the accumulation of cyclins (CCNs) and cyclin-dependent kinases (CDKs) complexes and degradation of CCNs. In human tumors, instead, the cell cycle is deregulated, causing absence of differentiation and aberrant cell growth. Oncogenic alterations of CCNs, CDKs, and CDKIs have been reported in more than 90% of human cancers, and the most frequent are those related to the G1 phase. Several molecular mechanisms, including gene overexpression, chromosomal translocations, point mutations, insertions and deletions, missense and frame shift mutation, splicing, or methylation, may be responsible for these alterations. The cell cycle regulators are involved in tumor progression given their association with cancers characterized by higher incidence of relapses and chemotherapy resistance. In the last decade anticancer drug researches focused on new compounds, able to target molecules related to changes in genes associated with tumor status. Recently, the studies have focused on the restoration of cell cycle control modulating molecular targets involved in cancer-cell alterations. This paper aims to correlate alterations of cell cycle regulators with human cancers and therapeutic responsivity.
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Wong, Gail A., Vincent Tang, Faten El-Sabeawy, and Robert H. Weiss. "BMP-2 inhibits proliferation of human aortic smooth muscle cells via p21Cip1/Waf1." American Journal of Physiology-Endocrinology and Metabolism 284, no. 5 (May 1, 2003): E972—E979. http://dx.doi.org/10.1152/ajpendo.00385.2002.
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Bone-morphogenetic proteins (BMP)-2 and -7, multifunctional members of the transforming growth factor (TGF)-β superfamily with powerful osteoinductive effects, cause cell cycle arrest in a variety of transformed cell lines by activating signaling cascades that involve several cyclin-dependent kinase inhibitors (CDKIs). CDKIs in the cip/kip family, p21Cip1/Waf1and p27Kip1, have been shown to negatively regulate the G1 cyclins and their partner cyclin-dependent kinase proteins, resulting in BMP-mediated growth arrest. Bone morphogens have also been associated with antiproliferative effects in vascular tissue by unknown mechanisms. We now show that BMP-2-mediated inhibition of platelet-derived growth factor (PDGF)-stimulated human aortic smooth muscle cell (HASMC) proliferation is accompanied by increased levels of p21 protein. Antisense oligodeoxynucleotides specific for p21 attenuate BMP-2-induced inhibition of proliferation when transfected into HASMCs, demonstrating that BMP-2 inhibits PDGF-stimulated proliferation of HASMCs through induction of p21. Whether p21-mediated induction of cell cycle arrest by BMP-2 sets the stage for osteogenic differentiation of vascular smooth muscle cells, ultimately leading to vascular mineralization, remains to be investigated.
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Liu, Wingsze, Coral Olazagasti, Chung-Shien Lee, Taylor Decina, Karalyn Pappas, and Kit Cheng. "A single institution retrospective study of the effect of starting doses in patients with ER-positive metastatic breast cancer on CDK 4/6 inhibitors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e13056-e13056. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e13056.
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e13056 Background: CDK4/6 inhibitors (CDKi) have become part of standard of care in the treatment ER-positive, Her2Neu negative of metastatic breast cancer (MBC). Hematologic toxicity from CDKi are common which can lead to dose interruption or dose reduction. There is limited data to compare those who started on full dose and those who started on a reduced dose CDKi. We sought to investigate the impact of reduced starting dose of CDKis. Methods: We conducted a single institution retrospective study on patients (pts) who were treated with CDKi from 2015 to 2019. In this subgroup analysis, we sought to determine the percentage of pts that started on reduced dose CDKi. Pts who were started on reduced dose were compared to those started on standard FDA dose CDKi. Rates of hematologic toxicities, dose interruptions, further dose reductions, progression-free survival and overall survival were compared between the two groups. Data from absolute neutrophil count, hemoglobin and platelet count on Days 1 and 15 of the first 2 cycles were graded for hematologic toxicity according to CTCAE v 5.0. Results: Out of 220 pts, 175 (79.6%) pts started on standard starting dose CDKi and 45 (20.5%) pts started on reduced dose CDKi. 30.86% of pts on the standard dosing group and 28.9% of pts on the reduced starting dose group had a dose interruption. The association between starting dose and dose interruption is not statistically significant (p < 0.86). The estimated 12-month survival rate is 95% (95% CI: 89% - 97%) for the pts on standard dose CDKi and 85% (95% CI: 67% - 93%) for the group reduced dose group. The estimated 12-month progression-free survival rate is 72% (95% CI: 64% - 78%) for the standard dosing group and 35% (95% CI: 21% - 50%) for the reduced dose group. Conclusions: Our study showed a significant survival rate and progression-free survival rate difference between patients who were started on standard FDA starting dose compared to those started on reduced dose CDKi.
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Perecin, F., S. C. Méo, C. L. V. Leal, and J. M. Garcia. "Oocyte activation and preimplantation development of bovine embryos obtained by specific inhibition of cyclin-dependent kinases." Arquivo Brasileiro de Medicina Veterinária e Zootecnia 59, no. 2 (April 2007): 280–87. http://dx.doi.org/10.1590/s0102-09352007000200002.
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The efficiency of bohemine and roscovitine in combination with ionomycin on parthenogenetic activation and initial embryonic development of bovine oocytes was studied. Two experiments were performed: in the first, different concentrations (0, 50, 75 or 100µM) and different exposure periods (2, 4 or 6 hours) to bohemine or roscovitine were tested for activation rates of in vitro matured (IVM) bovine oocytes, which were pre-exposed to ionomycin. The best treatments, 75µM bohemine and 50µM roscovitine, both for 6h, were used in the second experiment, in which IVM bovine oocytes were exposed to ionomycin, followed or not by bohemine or roscovitine treatment, and evaluated for nuclear status, activation rate and blastocyst development were assessed. The combined treatments (ionomycin + cyclin-dependent kinases inhibitors - CDKIs) showed better results for activation rates (77.3%) and initial embryonic development (35.2%) than the single ionomycin treatment (69.4% for activation and 21.9% for development); and also lead to a more uniform activation (nearly 90% single pronucleus development). The results showed that CDKIs improve the effects of ionomycin on parthenogenetic activation and blastocyst development in bovine oocytes and could help to achieve more efficient activation protocols, increasing the developmental competence of embryos obtained by reproductive biotechniques.
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Takeuchi, S., HP Koeffler, DR Hinton, I. Miyoshi, S. Melmed, and I. Shimon. "Mutation and expression analysis of the cyclin-dependent kinase inhibitor gene p27/Kip1 in pituitary tumors." Journal of Endocrinology 157, no. 2 (May 1, 1998): 337–41. http://dx.doi.org/10.1677/joe.0.1570337.
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By regulating cyclin-cyclin-dependent kinase (CDK) complex activity, individual CDK inhibitors (CDKIs) are potential tumor suppressors. One of the CDKIs, p27/Kip1, binds to a variety of CDK-cyclin complexes. A link between loss of p27/Kip1 function and development of pituitary tumors was suggested by the formation of pituitary tumors in almost all mice with germline deletion of the p27/Kip1 gene. However, genetic aberrations in the p27/Kip1 locus have not been analyzed in human pituitary tumors. We investigated eighteen non-functioning and GH-secreting pituitary tumor samples for p27/Kip1 mutations by single-strand conformational polymorphism (SSCP) following PCR. We found five abnormally migrating samples on the PCR-SSCP analysis. The sequence of these samples revealed a polymorphism of codon 109 (Val-->Gly), which has been previously described. No other structural changes of p27/Kip1 were found in these pituitary tumors within the coding region. In addition, no difference in p27/Kip1 protein levels in pituitary tumor tissues compared with normal pituitary tissues was demonstrated by immunostaining. These data suggest that both p27/Kip1 mutations and decreases in p27/Kip1 protein levels are infrequent in the development of pituitary tumors.
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Takeuchi, S., CR Bartram, T. Seriu, CW Miller, A. Tobler, JW Janssen, A. Reiter, WD Ludwig, M. Zimmermann, and J. Schwaller. "Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood." Blood 86, no. 2 (July 15, 1995): 755–60. http://dx.doi.org/10.1182/blood.v86.2.755.bloodjournal862755.
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A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor- suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.
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Howard, David, David James, Kate Murphy, Jezabel Garcia-Parra, Belen Pan-Castillo, Stuart Rex, Annemarie Moul, et al. "Dinaciclib, a Bimodal Agent Effective against Endometrial Cancer." Cancers 13, no. 5 (March 6, 2021): 1135. http://dx.doi.org/10.3390/cancers13051135.
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Endometrial cancer (EC) is the sixth most prevalent female cancer globally and although high rates of success are achieved when diagnosed at an early stage, the 5-year survival rate for cancers diagnosed at Stages II–IV is below 50%. Improving patient outcomes will necessitate the introduction of novel therapies to the clinic. Pan-cyclin-dependent kinase inhibitors (CDKis) have been explored as therapies for a range of cancers due to their ability to simultaneously target multiple key cellular processes, such as cell cycle progression, transcription, and DNA repair. Few studies, however, have reported on their potential for the treatment of EC. Herein, we examined the effects of the pan-CDKi dinaciclib in primary cells isolated directly from tumors and EC cell lines. Dinaciclib was shown to elicit a bimodal action in EC cell lines, disrupting both cell cycle progression and phosphorylation of the RNA polymerase carboxy terminal domain, with a concomitant reduction in Bcl-2 expression. Furthermore, the therapeutic potential of combining dinaciclib and cisplatin was explored, with the drugs demonstrating synergy at specific doses in Type I and Type II EC cell lines. Together, these results highlight the potential of dinaciclib for use as an effective EC therapy.
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Roman-Gomez, Jose, Juan Antonio Castillejo, Antonio Jimenez, Maria Gracia Gonzalez, Fernanda Moreno, Maria del Carmen Rodriguez, Manuel Barrios, Juan Maldonado, and Antonio Torres. "5′ CpG island hypermethylation is associated with transcriptional silencing of the p21CIP1/WAF1/SDI1 gene and confers poor prognosis in acute lymphoblastic leukemia." Blood 99, no. 7 (April 1, 2002): 2291–96. http://dx.doi.org/10.1182/blood.v99.7.2291.
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The p21 is a downstream effector of p53/p73 and belongs to the CIP/KIP family of cyclin-dependent kinase inhibitors (CDKIs). It is, therefore, a potential tumor suppressor gene and probably plays an important role in tumor development. Moreover, reduced expression of p21 has been reported to have prognostic value in several human malignancies. In contrast with other CDKIs, mutational inactivation of p21 is infrequent, but gene inactivation by an alternative mechanism seems to be the general pathway. In this study, we analyzed the methylation status of the p21 promoter region using semiquantitative polymerase chain reaction in 124 patients with acute lymphoblastic leukemia (ALL). We observed p21 hypermethylation in bone marrow cells from 41% (51 of 124) of ALL patients. Hypermethylation within promoter strongly correlated with decreased p21 messenger RNA expression in tumoral cells. Clinical, molecular, and laboratory features and complete remission rate did not differ significantly between hypermethylated and normally methylated patients. Estimated disease-free survival (DFS) and overall survival at 7 and 9 years, respectively, were 59% and 65% for healthy patients and 6% and 8% for hypermethylated patients (P = .00001 andP = .006). Multivariate analysis of potential prognostic factors demonstrated that p21 methylation status was an independent prognostic factor in predicting DFS (P = .0001). Our results indicate that the p21 gene is subject to methylation regulation at the transcription level in ALL and seems to be an important factor in predicting the clinical outcome of these patients.
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Semiglazov, V. F., M. A. Dzhelialova, S. S. Yerechshenko, E. T. Munaeva, R. S. Pesotsky, A. I. Tseluyko, A. S. Emelyanov, R. V. Donskikh, and P. V. Krivorotko. "Post-neoadjuvant treatment of breast cancer." Meditsinskiy sovet = Medical Council, no. 9 (July 30, 2020): 232–41. http://dx.doi.org/10.21518/2079-701x-2020-9-232-241.
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Achieving a pathologic complete response as a result of neoadjuvant treatment is associated with improved prognosis in breast cancer. The CREATE-X trial showed a significant survival improvement with capecitabine treatment of patients with residual invasive disease following neoadjuvant chemotherapy, and the KATHERINE trial demonstrated a significant benefit of trastuzumabemtansine (TDM1) in patients with HER2-positive breast cancer who did not achieve a pathologic complete response, so we have a lot of interesting alternatives of post-neoadjuvant treatments for high-risk patients. The discovery of molecular markers of resistance to endocrinotherapy (cyclin-dependent kinases (CDK 4/6), ER mutation (ESR1), mTOR signaling pathway, co-expression of ER+/HER2+) and inhibitors to them expanded the possibilities of endocrinotherapy not only in advanced and metastatic breast cancer, but also in residual ER+ tumors. The pCR rates in hormone receptor-positive breast cancer after neoadjuvant chemotherapy are around 10%, which is much lower than the values observed in HER2-positive and triple negative subtypes, so new strategies are needed to improve pCR rates in this subgroup, even though the adjuvant endocrine therapy impacts significantly the outcomes of this patients. The cyclin-dependent kinases (CDKs) are serine–threonine kinases that regulate cell cycle progression from the G1 to the S-phase during mitosis. CDKs activity can be abnormally increased or dysregulated in breast cancer, leading to a constant stimulus for cell proliferation and survival, which is a known mechanism of resistance to endocrine treatment. The CDK inhibitors act on CDKs and block their activity, thereby restoring the cell cycle regulation. In studies with metastatic hormone receptor-positive breast cancer patients, the combination of a CDKis with first or second-line endocrine therapy showed significant improvements in progression-free survival and response rates. Evolving techniques such as next-generation sequencing and gene expression profiles have improved our understanding of the biology of residual disease and also the mechanisms involved in treatment resistance.
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Moreno-Lorenzana, Dafne, Sócrates Avilés-Vazquez, Miguel Angel Sandoval Esquivel, Antonio Alvarado-Moreno, Vianney Ortiz-Navarrete, Héctor Torres-Martínez, Manuel Ayala-Sánchez, Héctor Mayani, and Antonieta Chavez-Gonzalez. "CDKIs p18INK4cand p57Kip2are involved in quiescence of CML leukemic stem cells after treatment with TKI." Cell Cycle 15, no. 9 (March 17, 2016): 1276–87. http://dx.doi.org/10.1080/15384101.2016.1160976.
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Guida, L., M. Annunziata, I. Passaro, C. Buonaiuto, R. Rullo, S. Tetè, F. Della Ragione, and A. Oliva. "Acetylsalicylic Acid Inhibits Proliferation of Human Bone Marrow Stromal Cells and Matrix Mineralization." International Journal of Immunopathology and Pharmacology 21, no. 4 (October 2008): 921–28. http://dx.doi.org/10.1177/039463200802100416.
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Acetylsalicylic acid (ASA) and other non-steroidal anti-inflammatory drugs have been shown to potentially inhibit bone healing and bone formation in both animal and clinical studies. Due to the extensive diffusion of ASA-based long-term therapies, the implications of such a side-effect are of interest in all types of bone surgery, including bone grafting procedures and dental implant placement. In this study, we investigate the effect of ASA at therapeutic concentrations on the proliferation and osteogenic differentiation of human bone marrow stromal cells (BMSCs). Primary cultures of BMSCs were isolated and expanded. Their proliferation in response to ASA 50, 100 and 200 μg/ml was evaluated by MTT assay and 3H-thymidine incorporation. Cell cycle machinery was also investigated by FACS and analysis of inhibitors of cyclin-dependent kinases (CDKIs). ASA inhibited BMSC proliferation and DNA synthesis in a dose-dependent manner down to 60% of control (ASA 200 μg/ml) at 72 h. Cell cycle analysis showed a decrease of BMSCs in the S and G2/M phases with a concomitant accumulation in GO/1 in ASA treated cells. The finding was associated to increased levels of some CDKIs, namely p27Kip1 and p21Cip1, whereas ASA did not affected p16Ink4A level at any of the concentrations employed. The matrix mineralization, that represents the major feature of the osteogenic commitment, was assessed by a specific staining procedure (von Kossa) and by calcium content determination. Both the methods demonstrated an extensive reduction (>90%) of extracellular calcification at 200 μg/ml ASA. On the basis of our results, we can hypothesize that the widely reported inhibition of bone healing by ASA might be sustained both by a direct anti-proliferative effect on BMSCs and by an alteration of the extracellular calcification.
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Chang, Mei-Yin, Den-En Shieh, Chung-Chi Chen, Ching-Sheng Yeh, and Huei-Ping Dong. "Linalool Induces Cell Cycle Arrest and Apoptosis in Leukemia Cells and Cervical Cancer Cells through CDKIs." International Journal of Molecular Sciences 16, no. 12 (November 26, 2015): 28169–79. http://dx.doi.org/10.3390/ijms161226089.
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Campbell, M. J., E. Elstner, S. Holden, M. Uskokovic, and H. P. Koeffler. "Inhibition of proliferation of prostate cancer cells by a 19-nor-hexafluoride vitamin D3 analogue involves the induction of p21waf1, p27kip1 and E-cadherin." Journal of Molecular Endocrinology 19, no. 1 (August 1997): 15–27. http://dx.doi.org/10.1677/jme.0.0190015.
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ABSTRACT We have synthesized and studied the ability of a series of seven novel 1α,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 ≈ 5 × 10−11 m). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 ≈ 2 × 10−8 m). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10−7 m) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.
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Amani, Jafar, Nassim Gorjizadeh, Simin Younesi, Mojtaba Najafi, Arash M. Ashrafi, Saeed Irian, Negar Gorjizadeh, and Khalil Azizian. "Cyclin-dependent kinase inhibitors (CDKIs) and the DNA damage response: The link between signaling pathways and cancer." DNA Repair 102 (June 2021): 103103. http://dx.doi.org/10.1016/j.dnarep.2021.103103.
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Chen, Jun, Frank Hong, and Perry D. Nisen. "Gene therapy for human brain tumors by ectopic overexpression of cell cycle cyclin-dependent kinase inhibitors (CDKIs) • 646." Pediatric Research 41 (April 1997): 110. http://dx.doi.org/10.1203/00006450-199704001-00666.
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Riera, María F., Mariana Regueira, María N. Galardo, Eliana H. Pellizzari, Silvina B. Meroni, and Selva B. Cigorraga. "Signal transduction pathways in FSH regulation of rat Sertoli cell proliferation." American Journal of Physiology-Endocrinology and Metabolism 302, no. 8 (April 15, 2012): E914—E923. http://dx.doi.org/10.1152/ajpendo.00477.2011.
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The final number of Sertoli cells reached during the proliferative periods determines sperm production capacity in adulthood. It is well known that FSH is the major Sertoli cell mitogen; however, little is known about the signal transduction pathways that regulate the proliferation of Sertoli cells. The hypothesis of this investigation was that FSH regulates proliferation through a PI3K/Akt/mTORC1 pathway, and additionally, AMPK-dependent mechanisms counteract FSH proliferative effects. The present study was performed in 8-day-old rat Sertoli cell cultures. The results presented herein show that FSH, in addition to increasing p-Akt, p-mTOR, and p-p70S6K levels, increases p-PRAS40 levels, probably contributing to improving mTORC1 signaling. Furthermore, the decrease in FSH-stimulated p-Akt, p-mTOR, p-p70S6K, and p-PRAS40 levels in the presence of wortmannin emphasizes the participation of PI3K in FSH signaling. Additionally, the inhibition of FSH-stimulated Sertoli cell proliferation by the effect of wortmannin and rapamycin point to the relevance of the PI3K/Akt/mTORC1 signaling pathway in the mitotic activity of FSH. On the other hand, by activating AMPK, several interesting observations were made. Activation of AMPK produced an increase in Raptor phosphorylation, a decrease in p70S6K phosphorylation, and a decrease in FSH-stimulated Sertoli cell proliferation. The decrease in FSH-stimulated cell proliferation was accompanied by an increased expression of the cyclin-dependent kinase inhibitors (CDKIs) p19INK4d, p21Cip1, and p27Kip1. In summary, it is concluded that FSH regulates Sertoli cell proliferation with the participation of a PI3K/Akt/mTORC1 pathway and that AMPK activation may be involved in the detention of proliferation by, at least in part, a decrease in mTORC1 signaling and an increase in CDKI expression.
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Freidkin, Ilya, Michal Herman, Ana Tobar, Avry Chagnac, Yaacov Ori, Asher Korzets, and Uzi Gafter. "Effects of histone deacetylase inhibitors on rat mesangial cells." American Journal of Physiology-Renal Physiology 298, no. 2 (February 2010): F426—F434. http://dx.doi.org/10.1152/ajprenal.00107.2009.
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Glomerular mesangial cells (MCs) proliferate and produce extracellular matrix proteins in many progressive renal diseases. Recently, histone deacetylase inhibitors (HDIs) were shown to have antiproliferative and antifibrogenic effects in some in vitro and in vivo models. Using the [3H]-thymidine incorporation test, we have found that the HDI trichostatin A (TSA) effectively inhibits MC growth at nontoxic nanomolar concentrations. Similarly, the HDI valproic acid also inhibited MCs proliferation. Cell-cycle analysis indicated an arrest in G0/G1 phase in response to TSA, which was accompanied by elevation in synthesis of the cyclin-dependent kinase inhibitors (CDKIs) p21/Waf1 and p27/Kip1. TSA treatment suppressed α-smooth muscle actin, transforming growth factor-β1, and collagen protein synthesis by MCs and induced myofibroblast-like appearance of proliferating MCs. In the in vivo model of the anti-Thy1.1-induced glomerulonephritis, TSA and valproic acid treatments significantly suppressed proteinuria. Collectively, these data suggest a therapeutic potential for HDIs in the treatment of mesangial proliferative diseases and glomerulosclerosis.
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Yang, Zhongfa, Karen Drumea, James Cormier, Junling Wang, Xuejun Zhu, and Alan G. Rosmarin. "Gabp Transcription Factor Is Required for Self-Renew and Proliferation of Hematopoietic Stem and Progenitor Cells." Blood 118, no. 21 (November 18, 2011): 1284. http://dx.doi.org/10.1182/blood.v118.21.1284.1284.
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Abstract Abstract 1284 GABP is an ets transcription factor that regulates genes which are required for normal hematopoietic development. In myeloid cells, GABP is an essential component of a retinoic acid-inducible enhanceosome that mediates granulocytic gene expression and, in lymphoid cells, GABP regulates expression of IL7-R and the essential transcription factor, Pax5. GABP is a tetrameric complex that includes GABPa, which binds DNA via its ets domain, and GABPb, which contains the transcription activation domain. Genetic disruption of mouse Gabpa caused early embryonic lethality. We created mice in which loxP recombination sites flank exons that encode the Gabpa ets domain, and bred them to mice that bear the Mx1Cre recombinase; injection with pIC induced Cre expression and efficiently deleted Gabpa in hematopoietic cells. One half of the Gabpa knock-out (KO) mice died within two weeks of pIC injection in association with widespread visceral hemorrhage. Gabpa KO mice exhibited a rapid loss of mature granulocytes, and residual myeloid cells exhibited myelodysplasia due, in part, to regulation by Gabp of the transcriptional repressor, Gfi-1. We used bone marrow transplantation to demonstrate that the defect in Gabpa null myeloid cells is cell intrinsic. Although hematopoietic progenitor cells in Gabpa KO bone marrow were decreased more than 100-fold compared to pIC treated control mice, there was not a statistically significant difference in the numbers of Lin−c-kit+Sca-1− hematopoietic stem cells (HSCs) between KO and control mice. Genetic disruption of Gfi-1 disruption in HSCs caused increased cell cycle activity – an effect that is diametrically opposite of the effect of Gabpa KO; this suggests that the effect of Gabpa on HSCs is not due to its control of Gfi-1. In contrast, Gabpa KO HSCs exhibited a marked decrease in cell cycle activity, but did not demonstrate increased apoptosis. The defects in S phase entry of Gabpa null HSCs are reminiscent of the cell cycle defects in Gabpa null fibroblasts, in which expression of Skp2 E3 ubiquitin ligase, which controls degradation of the cyclin dependent kinase inhibitors (CDKIs) p21 and p27, was markedly reduced following Gabpa disruption. We showed that Gabpa KO cells express reduced levels of Skp2. We propose that GABP controls self-renewal and proliferation of mouse bone marrow stem and progenitor cells, in part, through its regulation of Skp2. Thus, Gabpa is a key regulator of myeloid differentiation through its control of Gfi-1, but it is required for cell cycle activity of HSCs, by a distinct effect that may be due to its control of Skp2 and CDKIs. Disclosures: No relevant conflicts of interest to declare.
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Yao, Kevin C., Tadashi Komata, Yasuko Kondo, Takao Kanzawa, Seiji Kondo, and Isabelle M. Germano. "Molecular response of human glioblastoma multiforme cells to ionizing radiation: cell cycle arrest, modulation of cyclin-dependent kinase inhibitors, and autophagy." Journal of Neurosurgery 98, no. 2 (February 2003): 378–84. http://dx.doi.org/10.3171/jns.2003.98.2.0378.
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Object. Ionizing radiation is the gold-standard adjuvant treatment for glioblastoma multiforme (GBM), the most aggressive primary brain tumor. The mechanisms underlying neoplastic glial cell growth inhibition after administration of ionizing radiation, however, remain largely unknown. In this report, the authors characterize the response of GBM cells to ionizing radiation and elucidate factors that correlate with the radiosensitivity of these tumors. Methods. Six human GBM cell lines were subjected to increasing doses of radiation. Each demonstrated a dose-dependent suppression of cell proliferation. In the most radiosensitive cell line, the authors demonstrated a transient increase in the expression of the cyclin-dependent kinase inhibitors (CDKIs) p21 and p27, which corresponded with a G1 cell-cycle arrest. In contrast, the most radioresistant cell line demonstrated a decrease in p21 and p27 expression levels, which correlated with a failure to arrest. Apoptosis did not occur in any cell line following irradiation. Instead, autophagic cell changes were observed following administration of radiation, regardless of the relative radiosensitivity of the cell line. Conclusions. These findings elucidate some of the molecular responses of GBMs to irradiation and suggest novel targets for future therapy.
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Velázquez, Carolina, Esin Orhan, Imene Tabet, Lise Fenou, Laura Boudarel, William Jacot, Claude Sardet, and Charles Theillet. "Exploiting DNA Repair Defect in Triple Negative Breast Cancer Using CDK Inhibition Strategy." Medical Sciences Forum 3, no. 1 (January 29, 2021): 13. http://dx.doi.org/10.3390/iecc2021-09212.
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Triple-negative breast cancer (TNBC), representing 15% of breast carcinomas, is an aggressive breast cancer subtype with a high probability of metastasis and limited treatment options. Noticeably, BRCA-deficiency occurs in 25% of the TNBCs and results in deficient homologous recombination (HR) repair. Interestingly, PARP inhibitors (PARPi) have shown synthetic lethality in a BRCA-deficient context; however, their efficacy is frequently hampered by intrinsic or acquired resistance mechanisms involving restoration of the HR. In that regard, the role of some CDKs proven to regulate key HR actors was of interest to us. In this study, we aimed to understand the rewiring pathways determining resistance to PARPi in BRCA-deficient cancers and to assess the role of transcriptional regulating CDKs such as CDK7, CDK9, or CDK12 in the transcriptional regulation of key HR genes. Our ultimate goal was to determine whether and which CDK inhibitors could be effective approaches to repress HR gene expression and induce pharmacological HR-deficiency. As such, these CDK-inhibitors (CDKi) could be molecules of choice allowing sensitization of tumors that would otherwise respond poorly to DNA damaging treatment. With this purpose, we used in vitro and in vivo (PDX) models of TNBC and studied the attenuation of the HR response in tumor cells and PDX models treated with CDK-inhibitors. Our final aim was to determine the most efficient combination of CDKi and PARPi Our HR read outs were RAD51 and BRCA1 foci formation upon PARPi treatment. We also measured the modification of RNA and protein expression levels induced by CDKi treatment on a series of diagnostic HR genes (BRCA2, PALB2, ATR, FANCD2), as a measure of HR repression. We present data comparing the relative efficiency of three 3 CDKi; dinaciclib, NVP-2, and SR-4835, which have different specificities and inhibit different CDKs with variable efficacy.
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Fang, Jing, Lyndsey Bolanos, Juana Serrano-Lopez, Susanne Christie, Jose A. Cancelas, and Daniel T. Starczynowski. "TRAF6 Is Essential for Maintaining Hematopoietic Stem Cell Homeostasis." Blood 128, no. 22 (December 2, 2016): 568. http://dx.doi.org/10.1182/blood.v128.22.568.568.
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Abstract Tumor necrosis factor (TNF) receptor associated factor 6 (TRAF6), an E3 ubiquitin ligase downstream of Toll-like receptors (TLR), is required for mediating signals in response to foreign pathogens and stress molecules, and is implicated in the pathogenesis of MDS and AML. Although TLRs are expressed on normal HSC and TRAF6 is implicated in malignant HSC function, the normal physiological role of TRAF6 in HSC homeostasis and during hematopoiesis remains unknown. We find that TRAF6 is expressed in human and mouse HSPC (LT-HSC, ST-HSC, and MPP) at comparable or elevated levels relative to mature myeloid and lymphoid cells. To understand the role of TRAF6 in HSPC homeostasis, we generated hematopoietic-specific and inducible TRAF6 deleted mice by crossing Traf6-floxed with Vav-Cre (Traf6-HscKO) or Mx1-Cre (Traf6-iKO after PolyIC treatment) mice, respectively. Traf6-HscKO mice are born smaller and become moribund shortly after birth. Examination of peripheral blood (PB) and bone marrow (BM) revealed a significant expansion of myeloid cells and reduction of lymphoid cells. Moreover, moribund mice developed splenomegaly and extramedullary hematopoiesis. To determine whether the observed phenotype could be driven by loss of TRAF6 in mature myeloid cells, we generated mice in which TRAF6 is only deleted in myeloid cells by crossing Traf6-floxed with LysM-Cre mice (Traf6-MyKO). Interestingly, Traf6-MyKO mice did not develop myeloid expansion in the PB, BM, or spleen, indicating that TRAF6 plays a role in normal HSPC function. To determine the cell-intrinsic role of TRAF6 in hematopoiesis, we transplanted BM cells from Traf6-HscKO mice into lethally-irradiated recipient mice. The recipient mice with Traf6-HscKO BM cells similarly displayed myeloid-biased hematopoiesis in PB, BM, and spleens. Strikingly, LT-HSCs from Traf6-HscKO mice were significantly reduced in the BM of recipient mice. To exclude a possible effect of myeloid cells on the reduction in LT-HSC, we examined BM HSPC from Traf6-MyKO mice. Consistent with a role of TRAF6 in normal HSC function, the LT-HSC proportions and numbers were not affected in Traf6-MyKO mice. We next examined the functional consequences of deleting TRAF6 in HSC by performing competitive BM transplantation assays. Although initial homing to the BM was comparable between WT and Traf6-HscKO cells, the donor-derived chimerism of Traf6-HscKO cells was significantly reduced for myeloid and lymphoid populations 1 month post transplantation, and declined to below 5% after 4 months as compared with control mice. In addition, donor-derived HSC, HPC, and total BM cell chimerism of Traf6-HscKO cells was dramatically reduced. To examine the effects of TRAF6 deletion on HSC function after BM engraftment has been achieved, competitive BMT were performed with BM cells from Traf6-iKO mice. Upon deletion of Traf6 (PolyIC treatment 2 months post transplantation), total PB and BM chimerism, and chimerism of Traf6-deleted LT-HSC and HPC dramatically declined. Collectively, these findings indicate that TRAF6 is essential for normal HSPC function and homeostasis. To understand the function of TRAF6 in HSPC, HSC-enriched Lin-Sca1+Kit+(LSK) BM cells were isolated and examined for gene expression changes by RNA-sequencing. Genes directly implicated in cell cycle control were among the most differentially expressed in Traf6-deficient HSPC. Particularly, the cyclin-dependent kinase inhibitors (CDKIs) p21, p27 and p57 were significantly down-regulated in Traf6-deficient LSK cells as compared to normal LSK cells. CDKIs are negative regulators of cell cycle progression and involved in maintaining HSC quiescence. Consistent with the observed reduction in CDKI genes, LT-HSC and HPC (LSK) from Traf6-HscKO mice were less quiescent (lower proportion of G0 cells) and more actively cycling (higher proportion of G1/S/G2/M cells). Despite the established requirement of TRAF6 in myeloid and lymphoid cells during infection, our study uncovers a critical role of TRAF6 during normal HSC function and homeostasis. Our findings suggest that TRAF6 is a novel hematopoietic-requisite factor for maintaining HSC quiescence and controlling myeloid-biased differentiation. These findings reinforce the importance of innate immune pathway gene dosage and signaling requirements in normal and malignant HSPC. Disclosures No relevant conflicts of interest to declare.
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Trivellin, Giampaolo, Ricardo R. Correa, Maria Batsis, Fabio R. Faucz, Prashant Chittiboina, Ivana Bjelobaba, Darwin O. Larco, et al. "Screening for GPR101 defects in pediatric pituitary corticotropinomas." Endocrine-Related Cancer 23, no. 5 (May 2016): 357–65. http://dx.doi.org/10.1530/erc-16-0091.
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Cushing’s disease (CD) in children is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. In this study, we investigated the orphan G-protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormone secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we extracted DNA from peripheral blood and pituitary tumor samples (n=36). No increased GPR101 expression was observed in tumors compared with normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were observed. GPR101 is not overexpressed in ACTH-secreting tumors compared with NPs. In conclusion, rare germline GPR101 variant was found in one patient with CD, but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD.
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Beksac, Meral, Ender Soydan, Selami Kocak Toprak, Merih Kizil, Gulsah Kaygusuz, and Isinsu Kuzu. "Marrow Plasma Cell Immunohistochemical Expression Profiles of Cyclins (A, D1, D2, D3), Cyclin Dependent Kinase Inhibitors (p16, p21) and Ki67: Predictors of Survival in Patients with Multiple Myeloma." Blood 106, no. 11 (November 16, 2005): 5117. http://dx.doi.org/10.1182/blood.v106.11.5117.5117.
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Abstract Background: Recently Bergsagel et al have published a hierarchical model of myeloma evolution based on cytogenetics and Cyclin (Cy) profiles. Previously we had reported flow cytometric expression profiles of these Cy and CDKI’s in unsorted marrow samples (Blood98 (11): 4230,2001) but had not been able to detect the parallelism between Cy-CDKI’s which we observed in the normals in the myeloma patients. Aim: Here in this study we aimed to analyze the same Cy and CDKI’s in marrow plasma cells by multiparameter immunocytochemistry and to evaluate the association with clinical parameters and impact on survival. Patients and methods: Fourty five myeloma patients diagnosed in our department between 1998–2004, aged 57(33–79), M/F:29/16 whose bone marrow biopsy specimens could be retrieved were included in the analysis. All patients were treated with VAD or MP as first line treatment. Staining was performed using monoclonal antibodies: Cyclins A, D1, p16, p21 (LabVision), Cy D3(DAKO) and Cy D2 (Santa Cruz) with Zymed ABC Px Kit manualy or Ventana Benchmark automated immunostainer for secondary visualization. Results were reported as positive (equal or more than 20% of plasma cells) or negative (less than 20%). Results: expression results are: p16: 8/45, Cy D1: 10/45, Cy D2: 16/44, Cy D3: 3/45, Cy D(D1 or D2 or D3): 27/45, CyA:7/45, p21:7/43. Cyclins and their inhibitors were found to be expressed in different combinations by plasma cells. A decreased expression of Cy A or D and a relevant CDKI’s increased expression was evaluated as a low proliferative situation (P min). P min was observed 5/45 of the patients, resulted with 80% overall response and 100% survival at 5 years. On the contrary P max patients (high Cy and low CDKI expressing) were observed more frequently(19/45). 10/19 of these patients responded and performed 57% survival. P max and P intermediate patients(any combinations other than P min and P max) responded (7/17) and survived similarly. Figure Figure Prognostic factors such as age, B2MG and CRP were similar between P min, P max or P intermediate groups. Cy-CDKI patterns were associated with bone disease: P max patients had bone lesions more frequently (11/14) whereas P min patients had none( p=0.008). When we analyzed the role of Cy D1 as a prognostic factor on survival (OS), OS at 5 years was 80 vs 49% (p=0.85). Similar analysis for Cy D2 was:72 vs 35%(p= 0.04). Among the Cy D2 positive patients, presence of Ki67 was an adverse factor on 5 year OS: 50 vs 75% (p=0.01) but p16 did not show an impact. Multivariate analysis results will be presented later. Conclusion: Our results show that combining Cy and CDKI expression profiles compared to analysis with only Cy or CDKI, gives better information about the proliferative status and survival. The role of bone disease as a prognostic factor but not it’s association with cell cycle regulators have been shown before.