Academic literature on the topic 'Mcl-1/Bcl-XL'
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Journal articles on the topic "Mcl-1/Bcl-XL"
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Oh, Doyeun, Seongmin Yoon, Seonyang Park, and Jeehyeon Bae. "Differential Regulations and Roles of Mcl-1 and Bcl-Xl during Megakaryopoiesis." Blood 112, no. 11 (November 16, 2008): 4727. http://dx.doi.org/10.1182/blood.v112.11.4727.4727.
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Abstract Backgrounds: Platelet plays an essential role in thrombosis and hemostasis and is produced from hematopoietic stem cells through a serious of differentiation and maturation processes called megakaryopoiesis. The major factor known to control platelet formation is thrombopoietin (TPO), but recently more proteins including apoptosis regulators have been reported to involve in megakaryopoiesis. Evolutionally conserved Bcl-2 family proteins are central regulators of apoptosis. Antiapoptotic Bcl-2 subfamily comprised of Bcl-xL, Mcl-1, Bcl-2, Bcl-w, and Bfl-1 plays a pivotal role in controlling cell death and survival under various conditions. According a recent study, Bcl-xL is a key molecular clock that determines the life span of platelets, but the role and regulation of Bcl-2 members in megakaryopoiesis are largely unknown. Methods and Results: We have established an in vitro system of megakaryopoiesis and performed the profiling of Bcl-2 family genes during megakaryocytosis. We found that Bcl-xL and Mcl-1 were predominant molecules among other members of the pro-survival proteins as determined by quantitative RT-PCR. TPO differentially regulates Bcl-xL and Mcl-1 in Meg-01 cells, in which Bcl-xL protein was significantly up-regulated while the level of Mcl-1 was attenuated. Furthermore, the roles of Bcl-xL and Mcl-1 during megakaryopoiesis were determined by modulating the expression levels of two proteins. Overexpression of Mcl-1 prominently enhanced the viability of the cells, whereas the knockdown of Mcl-1 promoted apoptosis of the cells. In contrast, forced expression of Bcl-xL did not affect the cell survival but rather significantly stimulated differentiation of megakarycytes. Conclusion: Bcl-xL and Mcl-1 are likely essential molecules during megakaryopoiesis. Moreover, the present study implies that although both Bcl-xL and Mcl-1 are members of antiapoptotic Bcl-2 family that promote the survival of different cells, these two proteins have distinctive and non-redundant functions in megakaryocytes.
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Seyfried, Felix, Felix Uli Stirnweiß, Alexandra Niedermayer, Stefanie Enzenmüller, Rebecca Louise Hörl, Vera Münch, Stefan Köhrer, Klaus-Michael Debatin, and Lüder Hinrich Meyer. "Synergistic activity of combined inhibition of anti-apoptotic molecules in B-cell precursor ALL." Leukemia 36, no. 4 (January 14, 2022): 901–12. http://dx.doi.org/10.1038/s41375-021-01502-z.
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AbstractTargeting BCL-2, a key regulator of survival in B-cell malignancies including precursor B-cell acute lymphoblastic leukemia, has become a promising treatment strategy. However, given the redundancy of anti-apoptotic BCL-2 family proteins (BCL-2, BCL-XL, MCL-1), single targeting may not be sufficient. When analyzing the effects of BH3-mimetics selectively targeting BCL-XL and MCL-1 alone or in combination with the BCL-2 inhibitor venetoclax, heterogeneous sensitivity to either of these inhibitors was found in ALL cell lines and in patient-derived xenografts. Interestingly, some venetoclax-resistant leukemias were sensitive to the MCL-1-selective antagonist S63845 and/or BCL-XL-selective A-1331852 suggesting functional mutual substitution. Consequently, co-inhibition of BCL-2 and MCL-1 or BCL-XL resulted in synergistic apoptosis induction. Functional analysis by BH3-profiling and analysis of protein complexes revealed that venetoclax-treated ALL cells are dependent on MCL-1 and BCL-XL, indicating that MCL-1 or BCL-XL provide an Achilles heel in BCL-2-inhibited cells. The effect of combining BCL-2 and MCL-1 inhibition by venetoclax and S63845 was evaluated in vivo and strongly enhanced anti-leukemia activity was found in a pre-clinical patient-derived xenograft model. Our study offers in-depth molecular analysis of mutual substitution of BCL-2 family proteins in acute lymphoblastic leukemia and provides targets for combination treatment in vivo and in ongoing clinical studies.
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Debrincat, Marlyse A., Emma C. Josefsson, Chloé James, Katya J. Henley, Sarah Ellis, Marion Lebois, Kelly L. Betterman, et al. "Mcl-1 and Bcl-xL coordinately regulate megakaryocyte survival." Blood 119, no. 24 (June 14, 2012): 5850–58. http://dx.doi.org/10.1182/blood-2011-12-398834.
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Abstract Mature megakaryocytes depend on the function of Bcl-xL, a member of the Bcl-2 family of prosurvival proteins, to proceed safely through the process of platelet shedding. Despite this, loss of Bcl-xL does not prevent the growth and maturation of megakaryocytes, suggesting redundancy with other prosurvival proteins. We therefore generated mice with a megakaryocyte-specific deletion of Mcl-1, which is known to be expressed in megakaryocytes. Megakaryopoiesis, platelet production, and platelet lifespan were unperturbed in Mcl-1Pf4Δ/Pf4Δ animals. However, treatment with ABT-737, a BH3 mimetic compound that inhibits the prosurvival proteins Bcl-2, Bcl-xL, and Bcl-w resulted in the complete ablation of megakaryocytes and platelets. Genetic deletion of both Mcl-1 and Bcl-xL in megakaryocytes resulted in preweaning lethality. Megakaryopoiesis in Bcl-xPf4Δ/Pf4ΔMcl-1Pf4Δ/Pf4Δ embryos was severely compromised, and these animals exhibited ectopic bleeding. Our studies indicate that the combination of Bcl-xL and Mcl-1 is essential for the viability of the megakaryocyte lineage.
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Senichkin, Viacheslav V., Nikolay V. Pervushin, Alexey V. Zamaraev, Elena V. Sazonova, Anton P. Zuev, Alena Y. Streletskaia, Tatiana A. Prikazchikova, et al. "Bak and Bcl-xL Participate in Regulating Sensitivity of Solid Tumor Derived Cell Lines to Mcl-1 Inhibitors." Cancers 14, no. 1 (December 30, 2021): 181. http://dx.doi.org/10.3390/cancers14010181.
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BH3 mimetics represent a promising tool in cancer treatment. Recently, the drugs targeting the Mcl-1 protein progressed into clinical trials, and numerous studies are focused on the investigation of their activity in various preclinical models. We investigated two BH3 mimetics to Mcl-1, A1210477 and S63845, and found their different efficacies in on-target doses, despite the fact that both agents interacted with the target. Thus, S63845 induced apoptosis more effectively through a Bak-dependent mechanism. There was an increase in the level of Bcl-xL protein in cells with acquired resistance to Mcl-1 inhibition. Cell lines sensitive to S63845 demonstrated low expression of Bcl-xL. Tumor tissues from patients with lung adenocarcinoma were characterized by decreased Bcl-xL and increased Bak levels of both mRNA and proteins. Concomitant inhibition of Bcl-xL and Mcl-1 demonstrated dramatic cytotoxicity in six of seven studied cell lines. We proposed that co-targeting Bcl-xL and Mcl-1 might lead to a release of Bak, which cannot be neutralized by other anti-apoptotic proteins. Surprisingly, in Bak-knockout cells, inhibition of Mcl-1 and Bcl-xL still resulted in pronounced cell death, arguing against a sole role of Bak in the studied phenomenon. We demonstrate that Bak and Bcl-xL are co-factors for, respectively, sensitivity and resistance to Mcl-1 inhibition.
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Bernardo, Paul H., Thirunavukkarasu Sivaraman, Kah-Fei Wan, Jin Xu, Janarthanan Krishnamoorthy, Chun Meng Song, Liming Tian, et al. "Synthesis of a rhodanine-based compound library targeting Bcl-XL and Mcl-1." Pure and Applied Chemistry 83, no. 3 (February 5, 2011): 723–31. http://dx.doi.org/10.1351/pac-con-10-10-29.
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A small library of pyridine-based rhodanine analogues of BH3I-1 were synthesized and screened against B-cell lymphoma-extra large (Bcl-XL) and myeloid cell leukemia sequence 1 (Mcl-1) for the ability to displace 5-carboxyfluorescein-labeled Bak peptide (Flu-Bak). Differences in selectivity toward Bcl-XL and Mcl-1 were observed, and the binding modes of selected compounds were studied further. The results may be useful in designing potent small-molecule inhibitors of Bcl-XL and Mcl-1 as well as selective Mcl-1 inhibitors.
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Haselager, Marco V., Karoline Kielbassa, Johanna ter Burg, Danique J. C. Bax, Stacey M. Fernandes, Jannie Borst, Constantine Tam, et al. "Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL." Blood 136, no. 25 (December 17, 2020): 2918–26. http://dx.doi.org/10.1182/blood.2019004326.
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Abstract Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Because ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment, combined with dissecting functional interactions of Bcl-2 family members, in an in vitro model of venetoclax resistance. In the PB, recent LN emigrants had higher Bcl-XL and Mcl-1 expression than did cells immigrating back to the LN. Under ibrutinib treatment, this distinction collapsed; significantly, the pretreatment profile reappeared in patients who relapsed on ibrutinib. However, in response to venetoclax, Bcl-2 members displayed an early increase, underlining the different modes of action of these 2 drugs. Profiling by BH3 mimetics was performed in CLL cells fully resistant to venetoclax due to CD40-mediated induction of Bcl-XL, Mcl-1, and Bfl-1. Several dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL cells. Lastly, we demonstrated that proapoptotic Bim interacts with antiapoptotic Bcl-2 members in a sequential manner: Bcl-2 > Bcl-XL > Mcl-1 > Bfl-1. Combined, the data indicate that Bcl-XL is more important in venetoclax resistance than is Mcl-1 and provide biological rationale for potential synergy between ibrutinib and venetoclax.
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Geng, Xiangrong, Chenguang Wang, Ashley Wolfe, Ira Maine, Suhaib Abdelrahman, Carlos A. Murga-Zamalloa, and Ryan A. Wilcox. "Pre-Clinical Activity of Navitoclax in TCR-Driven and Non-ALCL Mature T-Cell Lymphomas." Blood 142, Supplement 1 (November 28, 2023): 4146. http://dx.doi.org/10.1182/blood-2023-174520.
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Background: In contrast to many B-cell lymphomas that highly express BCL-2, BCL-2 expression is observed in <50% of most mature T-cell lymphoma (MTCL) subtypes, although a clinical trial investigating venetoclax in BCL-2 positive relapsed/refractory PTCL is ongoing (NCT03552692). In contrast, BCL-xL and/or MCL-1 are expressed in the majority of MTCL. Consistent with these findings, MCL-1 expressing anaplastic large cell lymphomas (ALCL) and typical (non-ETP) T-ALL, which highly express BCL-xL, have been shown by BH3 profiling to be dependent upon MCL-1 or BCL-xL, respectively. Among the more common MTCL subtypes, including cutaneous T-cell lymphomas (CTCL), the extent to which BCL-2 family members are a therapeutic vulnerability is uncertain. However, we have previously demonstrated that antigen- and costimulatory receptor signaling promote the growth and survival of these lymphomas and confers resistance to chemotherapy, and in conventional (non-malignant) T cells, these same signals upregulate BCL-xL, which is required for their clonal expansion and escape from cell death following T-cell activation. Therefore, given the increasing availability of selective BH3 mimetics and the need for improved therapeutic strategies, we were motivated to examine BCL-2 family member dependencies in these lymphomas. Methods: Peptides generated from BH3-only proteins and selective BH3 mimetics were utilized to perform “BH3 profilng” in MTCL. Cell viability upon exposure to BH3 mimetics was determined using standard approaches. Results: To pre-clinically assess BCL-2 family member dependencies and the mitochondrial apoptotic pathway in T-cell lymphoproliferative neoplasms, we performed BH3 profiling in 17 cell lines. Peptides derived from BIM and PUMA, which are promiscuous, were utilized to assess the extent to which cells are “primed” for apoptosis. Differences in apoptotic priming were not observed across subtypes, and most cell lines examined were highly primed. We next examined the dependence on specific antiapoptotic proteins by BH3 profiling using BAD (antagonizes BCL-2, BCL-xL, and BCL-w), HRK (antagonizes BCL-xL), MS1 (antagonizes MCL-1), and FS1 (antagonizes A1/BFL-1) peptides. BCL-2 dependence was not observed in the T-cell lymphoma cell lines we examined. However, and in stark contrast, most non-ALCL cell lines were BCL-xL dependent, whereas ALCL cell lines were largely MCL-1 dependent. In an effort to further confirm these results, and examine the extent to which peptide-based BH3 profiling predicts sensitivity to selective BH3 mimetics in MTCL, cell lines were treated with venetoclax, A1155463 (a BCL-xL selective antagonist), navitoclax (a BCL-2/BCL-xL antagonist), or S63845 (MCL-1 antagonist), and cell viability determined. Consistent with peptide-based BH3 profiling, all cell lines examined were resistant to venetoclax. ALCL cell lines were largely MCL-1 dependent, whereas the non-ALCL cell lines examined were largely BCL-xL dependent. Therefore, we examined BCL-xL and MCL-1 expression in these cells and observed a strong association between BCL-xL expression and both cytochrome c release in response to HRK peptide and cell viability in the presence of A1155463. A similar association was observed between MCL-1 expression and sensitivity to MS1 and S63845. Transcriptionally profiled MTCL specimens were stratified by MTCL classification (ALCL vs. non-ALCL) and in keeping with the data obtained using cell lines increased BCL-xL expression was observed in non-ALCL MTCL subtypes. Given the observed association between BCL-xL expression and vulnerability to BCL-xL antagonists, we sought to examined mechanisms that promote its expression. Both TCR signaling and CD28 costimulation are exploited by non-ALCL subtypes. We examined the extent to which TCR/CD28 stimulation regulates BCL-xL transcription. In MTCL specimens, a significant increase in BCL-xL transcription and sensitization to Bcl-xL antagonism were observed upon TCR/CD28 stimulation. A TCR-dependent GEM model was utilized, demonstrating that these MTCL are Bcl-xL dependent and sensitive to navitoclax. Conclusions: These findings suggest that BCL-xL is a therapeutic vulnerability for MTCL subsets, particularly non-ALCL subtypes that are TCR dependent, and provide a robust pre-clinical rationale for future studies investigating navitoclax in these lymphomas.
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Saffari_Chaleshtori, Javad, Ehsan Heidari-Sureshjani, Fahimeh Moradi, and Esfandiar Heidarian. "The Effects of Thymoquinone on Viability, and Anti-apoptotic Factors (BCL-XL, BCL-2, MCL-1) in Prostate Cancer (PC3) Cells: An In Vitro and Computer-Simulated Environment Study." Advanced Pharmaceutical Bulletin 9, no. 3 (August 1, 2019): 490–96. http://dx.doi.org/10.15171/apb.2019.058.
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Purpose: Since active plant ingredients can induce apoptosis in many tumors, in this study we evaluate the apoptotic effects of thymoquinone (TQ) on PC3 cells. Also, we predicted the interaction of TQ with BCL-XL, BCL-2, and MCL-1anti-apoptotic factors by computer-simulated environment. Methods: PC3 cells were treated with different concentrations of TQ (0- 80 µM) and IC50 was determined using 3-(4, 5-dimethylthiaztol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay. Apoptotic and cytotoxicity effects of TQ were analyzed using flowcytometry and comet assay, respectively. Changes in energy and the molecular interactions of TQ with BCL-XL, BCL-2 and MCL-1 anti-apoptotic factors were investigated using simulation. Results: IC50 value was 40 µM. TQ led to the destruction of the genome of PC3 cells and inducing apoptosis. Molecular dynamics (MD) revealed that the root mean-square deviation (RMSD), root mean square fluctuation (RMSF), radius of gyration (Rg), and the number of hydrogen and hydrophobic bonds between TQ and residues of BCL-2, BCL-XL and MCL-1were significantly (P<0.001) changed. TQ makes a more stable and stronger connection with BCL-XL compared to BCL-2 and MCL-1 and inhibits BCL-XL non-competitively. Conclusion: Our results demonstrated that TQ not only led to apoptosis, at least partly, due to reduction in the Coil, Turn, and Bend structure of BCL-XL but also caused a decrease in the Rg and RMSD value of BCL-XL, MCL-1, and BCL-2.
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Eldering, Eric, Victor Peperzak, Hanneke ter Burg, Stacey M. Fernandes, Jennifer R. Brown, and Arnon P. Kater. "Bcl-2 Members As Drug Target and Biomarkers for Response to Ibrutinib and Venetoclax in CLL." Blood 128, no. 22 (December 2, 2016): 2043. http://dx.doi.org/10.1182/blood.v128.22.2043.2043.
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Abstract Introduction. BCL-2 family members are crucial determinants for survival in normal and malignant B cells. Venetoclax, the BCL-2 targeting drug, was recently clinically approved for CLL. CLL cells cycle between the lymph node (LN) and peripheral blood, and between those compartments display large changes in BCL-XL and MCL-1, which are not targeted by Venetoclax. However, novel BH3 mimetics specific for BCL-XL and MCL-1 are under preclinical development. Ibrutinib is a clinically successful BTK inhibitor that forces Chronic Lymphocytic Leukemia (CLL) cells out of the lymph node. After prolonged application resistance develops in a fraction of patients, who then show fast disease progression. Thus, both Venetoclax and Ibrutinib have potential drawbacks when applied as single agents. For long-term successful application of new drug combinations, it is crucial to understand BCL-2 member functionality of malignant B cells in relation to their normal counterparts. In parallel, we studied clinical samples of CLL patients under Ibrutinib or Venetoclax treatment for changes in BCL-2 family members. Experimental procedures. FACS sorting of tonsil B subsets, mRNA and protein profiling, co-culture of CLL cells, co-IP of BCL-2 members, cell death assays with BH3 mimetics specific for BCL-2, BCL-XL or MCL-1 (ABT-199, WEHI-539, A-1210477), intracellular FACS for BCL-2, BCL-XL and MCL-1 in CLL (CD19/CD5/CXCR4). Results.We mapped the clearly distinct expression profiles for BCL-2 members in tonsillar naïve, germinal center (GC), plasma (PC) and memory B cells, which translate into different BH3 mimetic sensitivity profiles. In brief, naïve and memory cells rely on BCL-2, GC cells on MCL-1, and PC on BCL-XL. These approaches were extended to primary CLL cells. In a LN model where cells are fully resistant to single agent ABT-199 due to induction of MCL-1, BCL-XL and BFL-1, we find that dual or triple BH3 mimetic combinations restore killing. Moreover, there is differential sensitivity to (combinations of) BH3 mimetics between healthy and malignant B cells, suggesting there is a therapeutic window. Furthermore, intracellular FACS staining for BCL-2, MCL-1, and BCL-XL was performed on patients treated with Ibrutinib or Venetoclax. In untreated patients, recent LN emigrants (CD5hi/CXCR4lo) have higher BCL-XL and MCL-1 expression than 'old' returning cells (CD5lo/CXCR4hi). This distinction collapses under Ibrutinib treatment, demonstrating that Ibrutinib affects pro-survival BCL-2 members in vivo. Interestingly, in patients that develop Ibrutinib resistance the MCL-1 or BCL-XL pre-treatment profile reappears. In contrast, under Venetoclax treatment BCL-2 member levels do not change and can even increase in some patients, underlining the different mode of action of the two drugs. The pattern differed among patients (n=5) and increases were observed for BCL-2, BCL-XL, or MCL-1. Conclusions. BH3 mimetics have not only found their way to the clinic, but can also be used as tools for BCL-2 functionality profiling. Secondly, our ex vivo data underline that combination treatment between (paired) BH3 mimetics and/or Ibrutinib may afford better long-term efficacy in CLL than single agents. Thirdly, BCL-2 members may be useful as biomarkers for response and progression. Disclosures Eldering: Roche: Research Funding; Gilead: Research Funding. Brown:Pharmacyclics: Consultancy; Abbvie: Consultancy; Roche: Consultancy; Genetech: Consultancy. Kater:Celgene: Research Funding.
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Eno, Colins O., Guoping Zhao, Kristen E. Olberding, and Chi Li. "The Bcl-2 proteins Noxa and Bcl-xL co-ordinately regulate oxidative stress-induced apoptosis." Biochemical Journal 444, no. 1 (April 26, 2012): 69–78. http://dx.doi.org/10.1042/bj20112023.
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Because the detailed molecular mechanisms by which oxidative stress induces apoptosis are not completely known, we investigated how the complex Bcl-2 protein network might regulate oxidative stress-induced apoptosis. Using MEFs (mouse embryonic fibroblasts), we found that the endogenous anti-apoptotic Bcl-2 protein Bcl-xL prevented apoptosis initiated by H2O2. The BH3 (Bcl-2 homology 3)-only Bcl-2 protein Noxa was required for H2O2-induced cell death and was the single BH3-only Bcl-2 protein whose pro-apoptotic activity was completely antagonized by endogenous Bcl-xL. Upon H2O2 treatment, Noxa mRNA displayed the greatest increase among BH3-only Bcl-2 proteins. Expression levels of the anti-apoptotic Bcl-2 protein Mcl-1 (myeloid cell leukaemia sequence 1), the primary binding target of Noxa, were reduced in H2O2-treated cells in a Noxa-dependent manner, and Mcl-1 overexpression was able to prevent H2O2-induced cell death in Bcl-xL-deficient MEF cells. Importantly, reduction of the expression of both Mcl-1 and Bcl-xL caused spontaneous cell death. These studies reveal a signalling pathway in which H2O2 activates Noxa, leading to a decrease in Mcl-1 and subsequent cell death in the absence of Bcl-xL expression. The results of the present study indicate that both anti- and pro-apoptotic Bcl-2 proteins co-operate to regulate oxidative stress-induced apoptosis.
Dissertations / Theses on the topic "Mcl-1/Bcl-XL"
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Geny, Charlotte. "Recherche d'inhibiteurs naturels des protéines anti-apoptotiques Bcl-xL et Mcl-1." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA114833/document.
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Dans le but de rechercher des inhibiteurs naturels des protéines anti-Apoptotiques Bcl-XL et Mcl-1, deux essais biologiques ont été mis au point sur Bcl-XL/Bak-CF et Mcl-1/Bid-CF. Ces deux tests utilisent la polarisation de fluorescence et sont basés sur la liaison d’un peptide pro-Apoptotique marqué à la fluorescéine (Bak-CF ou Bid-CF) avec une protéine anti-Apoptotique (Bcl-XL ou Mcl-1). Au total, près de 600 extraits de pantes, provenant de diverses régions du monde, ont été criblés sur les deux protéines Bcl-XL et Mcl-1 permettant de sélectionner les extraits acétate d’éthyle des écorces de Knema hookeriana (Myristicaceae) et de Fissistigma latifolium (Annonaceae). L’analyse chimique des constituants des écorces de K. hookeriana a conduit à l’isolement de 12 lipides phénoliques dont 6 n’avaient jamais été isolés d’un organisme vivant. Seuls les acides anacardiques ont révélé de très fortes inhibitions de l’interaction Bcl-XL/Bak-CF et Mcl-1/Bid-CF dans les essais par polarisation de fluorescence. Une étude plus approfondie des interactions entre le plus actif des produits et les protéines (Bcl-XL, Mcl-1, Bak et Bid) par RMN, a montré que la modulation des interactions Bcl-XL/Bak et Mcl-1/Bid n’est pas liée à l’affinité de l’acide anacardique pour les protéines Bcl-XL et Mcl-1 mais a une forte affinité pour les peptides Bid et Bak. Le fractionnement bioguidé de l’extrait AcOEt des écorces de F. latifolium a conduit à l’isolement d’une nouvelle chalcone prénylée, la (±)-Écarlottone possédant une dual activité sur les protéines, Bcl-XL et Mcl-1. Par la suite, le fractionnement "RMN-Guidé" a mené à l’isolement de 6 analoguesIn order to search for natural inhibitors of anti-Apoptotic protein Bcl-XL and Mcl-1, two bioassays were developed on Bcl-XL/Bak-CF and Mcl-1/Bid-CF. Both assays use fluorescent polarisation, and are based on binding of a fluorescein labeled pro-Apoptotic peptide (Bak-CF or-CF Bid) with an anti-Apoptotic protein (Bcl-XL or Mcl-1). Nearly 600 extracts from various parts of the world were screened on both Bcl-XL and Mcl-1 proteins to select the ethyl acetate bark extracts of Knema hookeriana (Myristicaceae) and Fissistigma latifolium (Annonaceae). The chemical analysis of the constituents of K. hookeriana has led to the isolation of 12 phenolic lipids. 6 of them were never isolated from a living organism. Only anacardic acids showed very strong inhibition of the interaction Bcl-XL/Bak-CF and Mcl-1/Bid-CF in fluorescent polarisation assays. Further study of the interactions between the most active anacardic acid and proteins (Bcl-XL, Mcl-1, Bak and Bid) by NMR showed that the modulation of Bcl-XL/Bak and Mcl-1/Bid is not related to the affinity of the compoun to the anti-Apoptotic proteins, Bcl-XL and Mcl-1 but to its affinity for peptides, Bid and Bak. The bioguided fractionation of the AcOEt bark extract of F. latifolium led to the isolation of a novel prenylated chalcone, (±)-Écarlottone having a dual activity on protein, Bcl-XL and Mcl-1. Subsequently, fractionation "NMR-Guided" led to the isolation of 6 new analogs
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Abou, samra Alma. "Conception, synthèse et évaluation biologique d’inhibiteurs des protéines anti-apoptotiques de la famille Bcl-2." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS390/document.
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La mitochondrie joue un rôle capital dans la mort cellulaire programmée ou apoptose par l’intermédiaire des protéines de la famille Bcl-2. Le dérèglement de l'apoptose dans de nombreux cancers fait de cette voie et des protéines de la famille Bcl-2 des cibles prometteuses pour la thérapie anti-cancéreuse. Le développement de petites molécules ciblant les protéines de la famille Bcl-2 s’est toutefois révélé être un grand défi, et peu d’entre elles ont atteint des études de phase clinique. Cependant, depuis une quinzaine d’années, grâce à des approches variées et souvent innovantes, des composés très actifs ont été développés. Plusieurs composés sont actuellement en essais clinique et une molécule, le venetoclax, a obtenu la première autorisation de mise sur le marché en avril 2016. Ce succès thérapeutique démontre que les protéines de la famille de Bcl-2 sont des cibles potentielles pour la thérapie anticancéreuse.Les substances naturelles sont une source importante de nouvelles molécules à structures originales, et de nombreux médicaments utilisés actuellement en chimiothérapie sont d’origine naturelle. La meiogynine A est un triterpène dimère qui a été isolé et synthétisé dans notre équipe. Ce composé possède une activité inhibitrice duale des protéines anti-apoptotiques Bcl-xL et Mcl-1. Des analogues de première et deuxième génération ont été élaborés par la suite, parmi lesquels, certains présentent une activité duale sub-micromolaire. Contrairement aux analogues de première génération, ces composés ne sont cependant pas cytotoxiques, probablement en raison de la présence d’une fonction ester sur la chaine latérale qui peut s’hydrolyser en un métabolite inactif.Mon projet de thèse vise à élaborer des analogues de troisième génération de la meiogynine A possédant une activité inhibitrice multiple sub-micromolaire des protéines anti-apoptotiques Bcl-xL, Mcl-1, Bcl-2 et cytotoxiques sur des lignées cellulaires surexprimant ces mêmes protéines. Pour cela, un essai biologique de mesure d’inhibition de l’interaction Bcl-2/Bim a été mis en place et robotisé afin d’évaluer l’activité biologique des composés synthétisés. De plus, la voie de synthèse bioinspirée d’un précurseur commun des nouveaux analogues a été mise au point à l’échelle de plusieurs grammes. Ce précurseur a permis d’élaborer différents analogues de troisième génération de la meiogynine A en réalisant des pharmacomodulations sur la chaîne latérale afin de remplacer la fonction ester des analogues de deuxième génération par un groupement stable et résistant in cellulo. Différentes séries ont été envisagées (alcènes, amines, amides, carbamates et triazoles). L’activité biologique des composés synthétisés a été évaluée sur les trois cibles in vitro. Finalement, des analyses de cytotoxicité pour les analogues les plus actifs ont été réalisées par nos collaborateurs à l’Institut Gustave RoussyApoptosis is used by multicellular organisms to regulate tissue homeostasis through the elimination of useless or potentially harmful cells. The key players of apoptosis are caspases, a family of proteases whose activation is induced by two major signalling pathways. One of these pathways (the intrinsic pathway) is regulated by the Bcl-2 family of proteins. In recent years, numerous studies have shown that overexpression of the antiapoptotic Bcl-2, Bcl-xL or Mcl-1 proteins is involved in the development of many kinds of cancers or confers resistance to apoptosis induced by standard anticancer therapies. Consequently, targeting this family of proteins is a highly promising strategy for tumour treatment.The feasibility of disrupting protein-protein interactions between anti- and pro-apoptotic members of the Bcl-2 family, using small-molecule inhibitors has been successfully established, and venetoclax was the first to obtain the FDA authorisation in April 2016 as an inhibitor of anti-apoptotic proteins of Bcl-2.Natural products are still playing a significant role in drug discovery and development process. Thus, from the 1940’s to date, 75% of the 175 small molecules used in cancer therapy, are either natural products or derivatives of natural compounds. Screening of plant extracts, marine organisms or microorganisms can provide highly original and functionalized bioactive molecules that are unlikely obtained by screening synthetic libraries. In fact, structural complexity is often a criterion of specificity for biological target.Meiogynin A is an original molecule isolated from a Malaysian Annonaceae and synthesized in our team in 2009. It exhibited a promising inhibitory activity of Bcl-2, Bcl-xL and Mcl-1, three anti-apoptotic proteins of Bcl-2 family whose overexpression is correlated with many cancers. 1st- and 2nd-generation analogs were further elaborated. Despite their remarkable affinity towards target proteins, 2nd-generation analogs lacked cytotoxicity, probably due to the presence of an ester linker that could undergo competitive hydrolysis in cellulo, leading to an inactive metabolite.We aim to develop 3rd-generation analogues of meiogynine A exhibiting high affinity towards multiple anti-apoptotic members of Bcl-2 family as well as cytotoxicity on cancer cells that overexpress these proteins. For this, a new fluorescence polarization inhibition test for Bcl-2/Bim interaction has been implemented, and meiogynine A and its analogues have been tested against the new interaction. In addition to Bcl-xL/Bak and Mcl-1/Bid interaction inhibition, these molecules showed an ability to inhibit Bcl-2/Bim interaction. Thus, they are considered multiple inhibitors.3rd-generation analogues of meiogynine A were obtained by pharmacomodulation of a common precursor that was synthesized on a gram-scale through a bioinspired Diels-Alder reaction. Several functional groups that have better stability in vivo than the ester group were anticipated, such as the amines, amides, carbamates and triazoles. Biological activity of the synthesized analogues was evaluated, and those presenting the best inhibitory profile were evaluated in cellulo by our collaborators in the Institut Gustave Roussy
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Thébault, Stéphanie. "Etude des complexes entre TCTP (Translationally Controlled Tumor Protein) et ses partenaires." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T024.
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La thématique du laboratoire de l’équipe d’Adam Telerman porte sur la réversion tumorale, un processus rare au cours duquel les cellules cancéreuses perdent leur phénotype malin, et deviennent des cellules dites révertantes. Plusieurs protéines clefs impliquées dans cette transformation ont été mises en évidence, dont TCTP (Translationally Controlled Tumor Protein). La protéine TCTP est également impliquée dans la régulation de l’apoptose en interagissant et en renforçant l’activité anti-apoptotique de Mcl-1 et de Bcl-xl, deux protéines appartenant à la famille des Bcl-2. Ce projet s’attache à comprendre en termes moléculaires le mode d’action de TCTP au cours de l’apoptoseAdam Telerman’s team research focuses on tumor reversion, a rare process in which cancer cells lose their malignant phenotype, and therefore become revertant. Many key proteins were showed to be involved in this transformation, including TCTP (translationally Controlled Tumor Protein). TCTP protein is also involved in apoptosis regulation by interacting and strengthening the anti-apoptotic activity of Mcl-1 and Bcl-xl, two proteins from Bcl-2 family
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Du, Boulay Courtney Jerome. "Virtual Screening for Inhibitors of Anti-apoptotic Proteins: DCK, BCL-XL, MCL-1, MDMX, and MDM2." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4664.
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←Within this dissertation the topic of virtual screening is discussed with regard to three different cancer targets and also a brief introduction of the tools used in virtual screening. In Chapter 1, the reader will be introduced to virtual screening and the programs that are used in virtual screening. In Chapter 2, the first of three projects are discussed. This project consists of the work that was done to find inhibitors of the P53 binding domain of MDMX. In this project the mobility of residues within the binding site of MDMX are discussed and the ways in which we attempted to model how drugs would bind two adjacent pockets within MDMX. In Chapter 3, the virtual screening and modeling work done for RING domain of MDM2 and MDMX is discussed. This work was done in conjunction with Moffitt Cancer Center in order to solve the 60 year old mystery of the mechanism of how thalidomide and possibly its analog lenalidomide caused children to be born limbless. Current thinking is that Cereblon through an unknown teratogenic mechanism activates an increase in FGF8. We suggest a mechanism that may happen in parallel that involves stabilization of MDM2 and the reduction of P63 levels. Chapter 4, the work that was done against the BH3 binding domain of MCL-1 is discussed in conjunction with collaboration with the Manetsch lab. In order to complete this screening the validation of IC50 values and then attempt to modify those products based upon the structure of MCL-1. Chapter 5 discusses the work done to find inhibitors of deoxycytidine kinase. All of these chapters taken together provide a brief overview of the computational work done produce inhibitors of Protein-Protein Interaction against three major cancer targets.
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Remeur, Camille. "Synthèse et évaluation biologique de dérivés de la meiogynine A, un produit naturel, qui ciblent la restauration de l'apoptose." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS158.
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L'apoptose, appelée aussi mort cellulaire programmée, est un processus physiologique qui permet d'éliminer les cellules endommagées ou superflues lors du développement cellulaire. Le phénomène d'échappement à l'apoptose est une caractéristique fondamentale d'une cellule cancéreuse. Une des voies d'induction principale de l'apoptose est contrôlée par la famille des protéines Bcl-2 qui comprend des protéines pro-apoptotiques (comme Bak ou Bid) et des protéines anti-apoptotiques (comme Bcl-xL, Bcl-2 et Mcl-1). Dans de nombreux cancers, certaines protéines anti-apoptotiques de cette famille sont surexprimées ce qui induit une inhibition de l'apoptose et une résistance aux traitements classiques. Cette famille de protéines est une cible stratégique et prometteuse pour développer une nouvelle classe d'agents anticancéreux. Notre équipe a entrepris un criblage d'extraits bruts de plantes d'origine géographique variée sur l'interaction Bcl-xL/Bak. Cette étude préliminaire a conduit à la caractérisation de la meiogynine A, un sesquiterpène dimère isolé des écorces de Meiogyne cylindrocarpa, une plante de Malaisie. Ce composé est un inhibiteur naturel de l'interaction entre Bcl-xL et le peptide Bak et entre Mcl-1 et le peptide Bid. La synthèse totale de la meiogynine A a été développée dans l'équipe et repose sur une cycloaddition de Diels-Alder entre un triène et un diénophile. Deux analogues de 1ère génération, où le cyclohexane a été remplacé par un cycle aromatique, ont été synthétisés et ont montré une bonne activité in vitro et in cellulo. Cependant, la cycloaddition de Diels-Alder est très longue. Dans un premier temps, afin d'améliorer la réactivité des triènes cibles et d'effectuer des relations structure activité au niveau de la partie "Sud" de la meiogynine A, la synthèse de triènes chlorés originaux diversement fonctionnalisés au niveau de la partie aromatique a été réalisée. Deux diénophiles différents ont également été synthétisés en vue de modifier la partie "Est" de la meiogynine A. Plusieurs analogues ont ainsi été obtenus et ont été évalués biologiquement sur les protéines anti-apoptotiques Bcl-xL et Mcl-1 sur des tests in vitro. Dans un deuxième temps, des études préliminaires de l'interaction protéine/ligand ont été commencées en synthétisant deux sondes photoactivablesApoptosis, or programmed death, is used by multicellular organisms to regulate tissue homeostasis through the elimination of useless or potentially harmful cells. One of the main apoptotic pathways is controlled by the Bcl-2 family of proteins. These proteins are divided into pro-apoptotic members (as Bak or Bid) and anti-apoptotic members (as Bcl-xL, Mcl-1 or Bcl-2). In some cancers, they are often overexpressed in many kinds of cancer or are involved in the resistance to chemotherapy. Targeting these proteins is a highly promising strategy for anticancer therapy that has emerged over the last decades. Our team underwent a bioassay-guided screening of various plants extracts. A few years ago, meiogynin A, a dimeric sesquiterpenoid was isolated from a Malaysian tree bark using a bioassay-guided screening. This compound is a natural bcl-xL and Mcl-1 inhibitor. Total synthesis of meiogynine A was developped by our team and the final step is a Diels-Alder cycloaddition reaction between a triene and a dienophile. Then, the synthesis of two anlogues was performed, where the cyclohexane is replaced by an aromatic, and they shown a good biological activity in vitro and in celullo. Nevertheless, the Diels-Alder reaction is very slow. In order to improve triene reactivity and to perform structure activity relationship in the south part of meiogynine A, the synthesis of various original chlorinated triene functionnalized in the aromatic was realised. Two differents dienophiles was synthesized in order to modify the east part of the molecule. Several analogues were obtained et were evaluated on Bcl-xL and Mcl-1 proteins.Also, preliminary studies on protein/ligand interaction was started by the synthesis of two photoactivable probes
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Timme, Cindy R. "Drug Resistance Mechanisms to Gamma-secretase Inhibitors in Human Colon Cancer Cells." Scholar Commons, 2013. http://scholarcommons.usf.edu/etd/4954.
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Colorectal cancer is the third leading cause of cancer-related mortality. Much progress has been achieved in combating this disease with surgical resection and chemotherapy in combination with targeted drugs. However, most metastatic patients develop drug resistance so new modalities of treatment are needed.
Notch signaling plays a vital role in intestinal homeostasis, self-renewal, and cell fate decisions during post-development and is activated in colorectal adenocarcinomas. Under debate is its role in carcinomas and metastatic disease. In theory, blocking Notch activation using gamma-secretase inhibitors (GSIs) may show efficacy alone or in combination with chemotherapy in the treatment of colon cancer.
In Chapter Three, we tested the capacity for GSIs to synergize with oxaliplatin in colon cancer cell lines and evaluated the underlying molecular mechanisms. GSI alone had no effect on colon cancer cell lines. Surprisingly, we show that GSIs blocked oxaliplatin-induced apoptosis through increased protein levels of the anti-apoptotic Bcl-2 proteins Mcl-1 and/or Bcl-xL. Restoration of apoptosis was achieved by blocking Mcl-1 and/or Bcl-xL with obatoclax (an anti-apoptotic Bcl-2 agonist) or siRNA. An unexpected result was the induction of cell death with the combination of GSI and obatoclax.
In Chapter Four, we examined the mechanism of GSI + obatoclax-mediated cell death. We found that apoptosis played a minimal role. Rather, we identified blockage of cytoprotective autophagy played a causative role. Interestingly, we also saw autophagy induction in GSI-treated cells, which could explain the insensitivity of colon cancer cells to GSI. When autophagy was blocked in GSI-treated cells, cells became sensitive to GSI and cell death was elicited. The mechanism by which induction of autophagy occurs in GSI- treated cells is an area for further research.
Overall, our work questions the validity of the use of GSIs in the treatment of colorectal cancers. We show that GSIs may block apoptosis and induce cytoprotective autophagy simultaneously, resulting in increased drug resistance and cellular survival. Whether these two cellular survival processes occurs in patients needs to be examined before GSIs can be utilized in a clinical setting. If so, these two hurdles must be overcome.
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Lheureux-Thelliez, Stéphanie. "Evaluation préclinique de thérapies dirigées contre Bcl-xL et Mcl-1 dans les cancers de l'ovaire : focus sur les molécules BH3-mimétiques." Caen, 2013. http://www.theses.fr/2013CAEN4076.
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Les cancers de l’ovaire sont dépendants de deux protéines anti-apoptotiques Bcl-xL et Mcl-1. Dans ce contexte, la molécule BH3-mimétique, ABT-737, ciblant Bcl-xL apparaît prometteuse, bien que son activité soit conditionnée in vitro à l’inactivation de Mcl-1. In vitro, l’ABT-737 a été inefficace en agent seul pour induire la mort cellulaire dans quatre lignes cellulaires. Les dérivés du platine sensibilisent à l’ABT-737 par diminution de l’expression de Mcl-1 ou par augmentation de l'expression des protéines pro-apoptotiques Noxa et, à une moindre mesure, Bim. Ex vivo, sur des tumeurs issues de patientes atteintes d’un cancer de l’ovaire, l’ABT-737 a induit en agent seul la mort cellulaire par apoptose massive et son efficacité n'a pas été significativement améliorée par sa combinaison au carboplatine. L'expression de Bim à l’état basal apparaît comme un biomarqueur pertinent qui pourrait être facilement utilisé en pratique clinique pour sélectionner les patientes pouvant bénéficier de l’ABT-263 dans le cadre d’un essai clinique. Nous avons aussi étudié in vivo l'intérêt de cibler la voie PI3K/Akt/mTOR pour surmonter la chimiorésistance. Le BEZ235, double inhibiteur de PI3K et mTOR, a induit une diminution homogène de la fixation tumorale du FDG dans un modèle de cancer ovarien platine résistant. Elle a été corrélée à une diminution significative de la prolifération cellulaire et une extinction significative de la voie PI3K/mTOR. Quatre jours après l’arrêt du traitement, la reprise tumorale a été objectivée et corrélée à l’imagerie par FDG PET/CT. Ces données suggèrent que le FDG PET/CT peut être un marqueur dans le suivi des thérapies ciblant la voie PI3K/mTOROvarian cancers are addicted to the anti-apoptotic proteins Bcl-xL and Mcl-1. In this context, the BH3-mimetic ABT 737 molecule appears therapeutically promising as it inhibits Bcl xL, although its activity in vitro is conditioned by Mcl-1 inactivation. In vitro, ABT-737 as a single agent was ineffective at promoting cell death in the four cell lines tested. Platinum compounds sensitize to ABT-737 by dose-dependently decreasing Mcl-1 expression or by increasing the expression of pro-apoptotic BH3-only proteins Noxa and, to a lower extent, Bim. Surprisingly in the ex vivo study on human ovarian cancer, we demonstrated that ABT-737 induced massive apoptotic cell death as a single agent and that its efficacy was not significantly improved when combined with carboplatin. Bim expression at baseline appears as a relevant biomarker that could be easily used in clinical practice for the selection of ovarian cancer patients in the development of a clinical trial using ABT-263. We also studied in vivo the interest of targeting the PI3K/Akt/mTOR pathway to overcome chemoresistance in ovarian cancer. BEZ235, a dual PI3K/mTOR inhibitor, induced a marked and homogeneous decrease in FDG uptake in a cisplatin-resistant ovarian cancer model, which was correlated to a significant decrease in cell proliferation and to a significant PI3K/mTOR pathways inhibition. Four days following treatment cessation, tumor recovery was observed and correlated to FDG SA-PET/CT findings. These data suggest that FDG PET could be of use for therapy monitoring of PI3K/mTOR inhibitors
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Lecerf, Charlotte. "Evaluation préclinique de siRNA d'intérêt thérapeutique ciblant les protéines anti-apoptotiques Bcl-xL et Mcl-1 pour le traitement des cancers de l'ovaire chimiorésistants." Caen, 2014. http://www.theses.fr/2014CAEN4066.
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La chimiorésistance est responsable du sombre pronostic des cancers ovariens. Parmi les mécanismes responsables, un défaut du contrôle de la mort cellulaire par apoptose est souvent observé. La surexpression de deux membres anti-apoptotiques de la famille Bcl-2, Bcl-xL et Mcl-1, provoque une forte protection contre l’apoptose et leur inhibition concomitante provoque une apoptose massive. La première partie de ma thèse a consisté à démontrer in vitro le rôle unique de ces protéines dans la protection des cellules cancéreuses ovariennes contre l’apoptose en inhibant deux à deux l’expression des membres anti-apoptotiques de la famille Bcl-2 par des siRNA. La seconde partie a concerné le développement d’une stratégie ARN interférence in vivo, pour inhiber simultanément l’expression de ces deux cibles dans des modèles de carcinose péritonéale et de tumeurs sous-cutanées de cancers ovariens établis chez la souris nude. L’intérêt de deux vecteurs non viraux, un second/premier polymère et l’atélocollagène, complexés aux siRNA administrés par voie IP ou IV avec différents protocoles d’administration, a été évalué. L’imagerie des siRNA radiomarqués nous a permis d’appréhender la distribution des siRNA ; leur effet a été évalué par étude de l’expression de leurs cibles et de l’induction de l’apoptose, ainsi que par imagerie par bioluminescence. Cependant, aucun protocole de vectorisation ne s’est révélé suffisamment efficace pour une application clinique. La troisième partie de ce manuscrit rapporte l’intérêt de l’imagerie TEP pour l’évaluation précoce de l’effet d’un inhibiteur de PI3K/mTOR, le BEZ-235, dans un modèle de tumeur ovarienne sous-cutanée chez le rat nudeChemoresistance is responsible for poor prognosis of ovarian cancers. As part of incriminated mechanisms, default of apoptosis cell death control is generally observed. The surexpression of two anti apoptotic members of Bcl-2 family proteins, Bcl-xL and Mcl-1, induces a strong protection against apoptosis and their concomitant inhibition induces massive apoptosis. The first part of my phD work consisted in demonstrating the in vitro unique role of these proteins for ovarian cancer cells protection from apoptosis, using siRNA-mediated side by side silencing of the expression of anti apoptotic members of Bcl-2 family. Second part of my work concerned the development of an in vivo RNA interference strategy to simultaneously inhibit expression of these targets in peritoneal carcinomatosis and subcutaneous ovarian tumors in nude mice. The nterest of two non-viral delivery systems, a second/first polymer and atelocollagen, complexed with siRNA administered by IV or IP route with different administration protocols was evaluated. Radiolabeled siRNA imaging allowed apprehension of siRNA distribution, and their effect was evaluated by studying targets expression and apoptosis induction as well as by bioluminescent imaging. Nevertheless, no vectorization protocol revealed adequate efficiency for clinical translation. Third part of this manuscript relates PET imaging interest for early evaluation of the effect of a PI3K/mTOR inhibitor, BEZ 235, in subcutaneous ovarian tumor in nude rat
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Dardenne, Jérémy. "Premières pharmacomodulations de la meiogynine A, un sesquiterpène dimère inhibiteur de l’interaction Bcl-xL/Bak, régulant l’apoptose." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA114852/document.
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La régulation de l’apoptose fait partie des nouvelles cibles thérapeutiques dans la lutte contre le cancer. L’apoptose est l’autodestruction programmée des cellules qui, suite à un besoin physiologique, permet de réguler le développement des cellules. Dans de nombreux cancers, ce mécanisme est inhibé par une surexpression des protéines anti-apoptotiques de la famille Bcl-2 comme Bcl-xL et Mcl-1. Ce phénomène entraîne le développement des cellules tumorales et des résistances aux chimiothérapies. Dans cette optique, notre équipe à l’Institut de Chimie des Substances Naturelles a développé un criblage de plantes tropicales sur ces cibles. Des écorces d’une annonacée de Malaisie, Meiogyne Cylindrocarpa, a été isolé un sesquiterpène dimère, la meiogynine A, présentant une bonne affinité vis-à-vis de Bcl-xL (Ki = 10.7 M). Sa synthèse totale a été réalisée au laboratoire afin de déterminer sa configuration absolue et d’étudier les premières relations structure activité. Un de ses diastéréoisomères a également présenté une bonne affinité vis-à-vis de la protéine Bcl-xL.Afin d’étudier et d’approfondir les premières relations structure activité, la modulation de la meiogynine A a été réalisée. La synthèse des diénophiles acides a été optimisée afin de conduire majoritairement aux diénophiles précurseurs des composés actifs. Différents triènes ont également été synthétisés au laboratoire en vue de modifier la partie Sud de la meiogynine A. Plusieurs analogues ont ainsi pu être obtenus et ont été évalués biologiquement sur des tests in vitro et ex vivo. Des études de modélisation moléculaire et de RMN structurale ont également été réaliséesThe control of the apoptosis is one of the new modern key to fight against the cancer. The apoptosis is the self destruction of cells, part of the homeostasis, which regulates the cell developement. In several cancers, the over-expression of anti-apoptotic proteins, as Bcl-xL and Mcl-1 parts of the Bcl-2 proteins family, inhibate this naturel process. This phenomenum induce the tumoral cells developement and the chemotherapy’s resistance. In order to find new compounds which can regulate the apoptosis, our group in the Institut de Chimie des Substances Naturelles has screened different tropical plants on these targets. A Malaysian plant, Meiogynine Cylindrocarpa, was selected and the phyotchemist work on this plant gave us a new sesquiterpen , the meiogynin A (Ki = 10.7 M on Bcl-xL). Its total synthesis was realised in our laboratory in order to determine its absolute configuration and find the first structure activity relation. One of the synthetised diastereoisomers has presented a better affinity toward the protein. In order to precise these first structure activity relations, the modulation of the meiogynin A was initiated. The synthesis of the acid dienophiles was optimised, the main compounds are the precursors of the active decalins. New triene was also obtained in order to modulate the South Part of the meiogynin A. Thanks to a Diels-Alder reaction, these precursors were combined in order to form new analogues of the meiogynin A. All these compounds were biologically tested (in vitro et ex vivo). Experiments of molecular docking and 2D NMR were also realised
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Choudhary, Gaurav Sudhakar. "Role of Myeloid Cell Leukemia 1 (MCL-1) in mediating chemoresistance towards BCL-2 homology 3 (BH3) mimetics in lymphoid malignancies." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1448024862.
Full textConference papers on the topic "Mcl-1/Bcl-XL"
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Lam, Lloyd T., Haichao Zhang, John Xue, Paul Hessler, Stephen K. Tahir, Jun Chen, Sha Jin, Andrew J. Souers, and Joel D. Leverson. "Abstract 2759: Colorectal cancer cell lines with high BCL-XL and low MCL-1 expression are sensitive to a potent and selective BCL-XL inhibitor." In Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA. American Association for Cancer Research, 2014. http://dx.doi.org/10.1158/1538-7445.am2014-2759.
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Greaves, G., M. Milani, D. Byrne, R. Carter, M. Butterworth, X. Luo, P. Eyers, G. Cohen, and S. Varadarajan. "PO-061 BCL-2 family of proteins, BCL-XL and MCL-1, regulate apoptosis and cancer cell survival by different mechanisms." In Abstracts of the 25th Biennial Congress of the European Association for Cancer Research, Amsterdam, The Netherlands, 30 June – 3 July 2018. BMJ Publishing Group Ltd, 2018. http://dx.doi.org/10.1136/esmoopen-2018-eacr25.105.
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Streator, Ashley, Eneida C. Villanueva, Burton F. Holmes, and Liping Zhang. "Abstract 4656: Assessment of BCL-2, BCL-xL and MCL-1 in bone marrow biopsy samples using VENTANA BenchMark XT automated slide stainer." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-4656.
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Coffee, Erin M., Anthony C. Faber, Carlotta Costa, Anahita Dastur, Hiromichi Ebi, Aaron N. Hata, Alan T. Yeo, et al. "Abstract C263: mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1." In Abstracts: AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics--Oct 19-23, 2013; Boston, MA. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1535-7163.targ-13-c263.
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Rahman, Siti Fairus Abdul, Kalaivani Muniandy, Ghows Azzam, and Nethia Mohana Kumaran. "Abstract 65: Anti-apoptotic proteins BCL-XL and MCL-1 are crucial for nasopharyngeal carcinoma (NPC) cell survival." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-65.
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Mester-Pavel, Patricia, Elisabeth Aschenbrenner, Vlad Pavel, Claudia Kunst, Karsten Gülow, and Martina Müller-Schilling. "Combination of panobinostat and bleomycin induces apoptosis in Hepatocellular Carcinoma (HCC) through downregulation of Bcl-XL and Mcl-1." In 39. Jahrestagung der Deutschen Arbeitsgemeinschaft zum Studium der Leber. Georg Thieme Verlag, 2023. http://dx.doi.org/10.1055/s-0042-1760016.
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Guo, Jun, Lisa Roberts, Jeffrey B. Kraft, Philip J. Merta, Keith B. Glaser, and Omar J. Shah. "Abstract 12:JAK2V617Fdrives Mcl-1 expression and sensitizes acute myeloid leukemia cells to dual inhibition of JAK2 and Bcl-XL." In Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL. American Association for Cancer Research, 2011. http://dx.doi.org/10.1158/1538-7445.am2011-12.
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Drapkin, Benjamin J., Sneha Sanghavi, David T. Myers, Jun Zhong, Sarah Phat, Youzhen Wang, Ensar Halilovic, et al. "Abstract 381: Combined inhibition of Bcl-2 and MCL-1 in small cell lung cancer (SCLC) is most effective in tumors with low Bcl-xL expression." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-381.
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Drapkin, Benjamin J., Sneha Sanghavi, David T. Myers, Jun Zhong, Sarah Phat, Youzhen Wang, Ensar Halilovic, et al. "Abstract 381: Combined inhibition of Bcl-2 and MCL-1 in small cell lung cancer (SCLC) is most effective in tumors with low Bcl-xL expression." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.sabcs18-381.
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Gao, Yang. "Abstract 2064: SF3B1 inhibitors sensitize head and neck squamous cell carcinoma to Bcl-xL inhibition by regulating Mcl-1 alternative splicing." In Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC. American Association for Cancer Research, 2013. http://dx.doi.org/10.1158/1538-7445.am2013-2064.
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