Relevant bibliographies by topics / LFM-A13

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Academic literature on the topic 'LFM-A13'

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Published: 9 March 2023

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Journal articles on the topic "LFM-A13"

1

Bam, Rakesh, Angela Pennisi, Xin Li, Sharmin Khan, Yuping Wang, Wen Ling, Bart Barlogie, John Shaughnessy, and Shmuel Yaccoby. "Bruton's Tyrosine Kinase (BTK) Is Indispensable for Myeloma Cell Migration towards SDF-1 and Induction of Osteoclastogenesis and Osteolytic Bone Disease." Blood 116, no. 21 (November 19, 2010): 447. http://dx.doi.org/10.1182/blood.v116.21.447.447.

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Abstract Abstract 447 Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase of the TEC family of protein tyrosine kinases, is preferentially expressed in the hematopoietic cells and involved in B-lymphocytes survival and differentiation, and their migration towards SDF-1 gradient. BTK is also expressed in osteoclast precursors and plays indispensable role in osteoclastogenesis (Shinohara et al., Cell 2008). LFM-A13 is small molecule inhibitor of BTK and TEC, and can be tolerated even when animals are given daily dose of 100 mg/kg. The aims of the study were to investigate the effect of LFM-A13 on myeloma cell migration and growth in vitro, and on myeloma bone disease and tumor growth in the SCID-rab model. Our clinical gene expression profiling data indicate that in contrast to most myeloma cell lines, primary myeloma cells express BTK and that relative to normal plasma cells, BTK expression is upregulated in myeloma cells molecularly classified in the CD-1, CD-2, HY, LB and MF subtypes. Expression of BTK at the RNA and proteins levels in myeloma cells and osteoclast precursors was validated using qRT-PCR and Western Blot. To test effect on migration, myeloma cells expressing BTK and cell surface CXCR4 (n=5) were placed in the top of transwell inserts in the absence and presence of LFM-A13 (50 μM) and their migration towards SDF-1 (30 nM) was evaluated after 18 hours. SDF-1 induced migration of myeloma cells by >2.5 folds, an effect that was markedly inhibited by LFM-A13 (p<0.01). At similar concentration, this agent modestly reduced growth of BTK-expressing myeloma cells by 20%, assessed by MTT assay. LFM-A13 dose dependently inhibited osteoclast formation by 25% at 10 μM (p<0.0005) and by 80% at 40 μM (p<0.0001). In vivo, SCID-rab mice engrafted with a novel myeloma cell line, DAS, established through sequential passaging in this animal model (Xin et al., BJH 2007). DAS cells do not grow in culture, are molecularly classified as MF subtype and express high level of BTK. Upon establishment of myeloma growth, 2 weeks after tumor cell injection, hosts were intraperitoneally treated with 40 mg/kg LFM-A13 or vehicle (10 mice/group) twice a day for 3 weeks. Myeloma bone disease was evaluated by x-rays and analysis of bone mineral density (BMD). Tumor growth was analyzed by measurement of circulating human Ig and histologically. Whereas in the control group BMD of the implanted bone was reduced by 15±4% from pretreatment levels, it remained unchanged (0.8±4% change from pretreatment level) in the LFM-A13 treated hosts (p<0.01 versus control). X-ray radiographs revealed induction of osteolytic lesions in implanted bones of control hosts and that LFM-A13 effectively prevented these effects. LFM-A13 reduced the number of TRAP-expressing osteoclasts in myelomatous bones by >43% (p<0.004). At the end of the experiment, tumor burden was insignificantly lower in hosts treated with the LFM-A13 (Ig levels 42±15 and 19±5 μg/ml in control and LFM-A13 groups, respectively). We conclude that BTK is indispensable for SDF-1-indcued myeloma cell migration and stimulation of osteoclastogenesis, and that pharmacologic inhibition of BTK effectively inhibits myeloma-induced bone resorption and may interrupt with myeloma cell homing and metastasis to bone. Disclosures: No relevant conflicts of interest to declare.
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Akker, E. van den, T. B. van Dijk, U. Schmidt, L. Felida, H. Beug, B. Löwenberg, and M. von Lindern. "The Btk inhibitor LFM-A13 is a potent inhibitor of Jak2 kinase activity." Biological Chemistry 385, no. 5 (May 14, 2004): 409–13. http://dx.doi.org/10.1515/bc.2004.045.

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AbstractLFMA13, or α-cyano-β-hydroxy-β-methyl-N-(2,5-dibromophenyl)propenamide, was shown to inhibit Brutons tyrosine kinase (Btk). Here we show that LFM-A13 efficiently inhibits erythropoietin (Epo)-induced phosphorylation of the erythropoietin receptor, Janus kinase 2 (Jak2) and downstream signalling molecules. However, the tyrosine kinase activity of immunoprecipitated or in vitro translated Btk and Jak2 was equally inhibited by LFM-A13 in in vitro kinase assays. Finally, Epo-induced signal transduction was also inhibited in cells lacking Btk. Taken together, we conclude that LFM-A13 is a potent inhibitor of Jak2 and cannot be used as a specific tyrosine kinase inhibitor to study the role of Btk in Jak2-dependent cytokine signalling.
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Zhang, Wei, Ping Zhou, Xiao Jiang, Zhe Fan, Xingxin Xu, and Fei Wang. "Negative Regulation of Tec Kinase Alleviates LPS-Induced Acute Kidney Injury in Mice via theTLR4/NF-κB Signaling Pathway." BioMed Research International 2020 (June 20, 2020): 1–15. http://dx.doi.org/10.1155/2020/3152043.

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Tec kinase is an important mediator in inflammatory immune response that enhances the activity of neutrophils and macrophages. However, information on its function in lipopolysaccharide- (LPS-) induced acute kidney injury (AKI) is limited. This study is aimed at determining whether Tec kinase was a regulator in AKI. An AKI model in mice was successfully established using intraperitoneal LPS. Results showed that the serum levels of creatinine (Cr), blood urea nitrogen (BUN), and cystatin-C (Cys-C) increased after intraperitoneal LPS injection. Renal tissue sustained significantly severe injury as measured by pathological scores. Pretreatment with LFM-A13 improved the function of the kidney in mice and decreased the renal injury score. Enzyme-linked immunosorbent assay showed that LFM-A13 significantly reduced the release of IL-1β and TNF-α in mice exposed to LPS. LFM-A13 can evidently abrogate the expression of Tec protein, MyD88, TLR4, NF-κB p65, and Tec’s phosphorylated protein as determined by Western blot. Immunohistochemistry analysis revealed that LFM-A13 markedly downregulated the expression of Tec kinase in renal tubular epithelial cells. In vitro, Tec kinase protein was expressed highly in NRK-52E cells after LPS exposure. Tec-siRNA also decreased IL-1β and TNF-α production and obviously abolished phospho-p65 and phospho-IκBα expression in NRK-52E cell stimulated by LPS; however, Tec-siRNA increased the IκBα level. Altogether, these data suggested that Tec kinase can be a modulating protein in AKI through TLR4/NF-κB activation.
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Bam, Rakesh, Wen Ling, Sharmin Khan, Angela Pennisi, Sathisha Upparahalli Venkateshaiah, Xin Li, Ryan Williams, et al. "Cell Surface CXCR4 and BTK Expression Are Associated in Myeloma Cells and Osteoclast Precursors and Mediate Myeloma Cell Homing and Clonogenicity, and Osteoclastogenesis." Blood 118, no. 21 (November 18, 2011): 884. http://dx.doi.org/10.1182/blood.v118.21.884.884.

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Abstract Abstract 884 Myeloma cells typically grow in bone, recruit osteoclast precursors and induce their differentiation and activity in areas adjacent to tumor foci. Clonal B-lymphocytes and plasma cells harboring lymphocytic phenotypes have a proposed role in sustaining myeloma. Bruton's tyrosine kinase (BTK) is expressed in hematopoietic cells and is particularly involved in B-lymphocyte function and osteoclastogenesis. The SDF-1/CXCR4 signaling pathway is reportedly involved in homing to bone of myeloma cells and osteoclast precursors. The aims of the study were to investigate the possible association between CXCR4 and BTK signaling in myeloma cells and osteoclast precursors, and the consequences of BTK inhibition on myeloma cell migration and clonogenicity, and osteoclastogenesis. By global gene expression profiling (GEP), BTK expression was moderately higher in clinical myeloma cells (n=559) than normal plasma cells (n=25, p<0.05). BTK was also detected in IL6–dependent cell lines and myeloma cell lines that can passage in vivo (n=7), using GEP, qRT-PCR and Western Blot analyses. Cell surface CXCR4 determined by flow cytometry was variably expressed in myeloma cells (5%–95%) and was significantly correlated with BTK gene expression (r=0.75, p<0.002, n=14). Most myeloma cell lines grown independently in vitro expressed very low levels of BTK; however, even in such cell lines (e.g. CAG), enrichment of myeloma cells expressing cell-surface CXCR4 by FACS analysis resulted in detectable BTK expression. BTK inhibition by shRNA in IL6–dependent INA6 cells inhibited their migration toward SDF-1 by >50% (p<0.006) and diminished their ability to form colonies in a 2-weeks clonogenic assay (p<0.0002). The BTK small molecule inhibitor LFM-A13 (25–50 μM) consistently reduced SDF-1-induced migration of primary myeloma cells and myeloma lines (n=6, p<0.03), and clonogenicity (colonies number and size) of 3 BTK-expressing myeloma lines by >50% (p<0.03). Using kinase immunoprecipitation assay, SDF-1 rapidly induced BTK phosphorylation (activation) in myeloma cells, an effect that was blocked by LFM-A13. In vivo, pretreatment of luciferase-expressing myeloma cells with LFM-A13 lessened their homing to bone following intravenous injection into SCID-rab mice as determined by live-animal imaging. BTK was highly expressed in osteoclast precursors while cell surface CXCR4 was detected in 5% of this cell population. LFM-A13 also reduced osteoclast precursor migration toward SDF-1 and suppressed osteoclast formation and bone resorption activity on dentine slices (p<0.002). In myeloma-bearing SCID-rab mice, LFM-A13 (n=10, 40 mg/kg, twice daily for 3 weeks, i.p.) reduced osteoclast number by 45% (p<0.004), prevented reduction of bone mineral density (BMD, p<0.04) and attenuated myeloma growth at near significant level (p<0.07). These data indicate that CXCR4 and BTK signaling are linked in myeloma cells and osteoclast precursors and that BTK has potential as a targeted myeloma therapy because of its roles in myeloma cell homing and clonogenicity and myeloma-induced osteolysis. Disclosures: Barlogie: Celgene, Genzyme, Novartis, Millennium: Consultancy, Honoraria, Patents & Royalties. Shaughnessy:Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties.
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Wang, Gaiqing, Zhenni Guo, Lusha Tong, Fang Xue, Paul R. Krafft, Enkhjargal Budbazar, John H. Zhang, and Jiping Tang. "TLR7 (Toll-Like Receptor 7) Facilitates Heme Scavenging Through the BTK (Bruton Tyrosine Kinase)–CRT (Calreticulin)–LRP1 (Low-Density Lipoprotein Receptor–Related Protein-1)–Hx (Hemopexin) Pathway in Murine Intracerebral Hemorrhage." Stroke 49, no. 12 (December 2018): 3020–29. http://dx.doi.org/10.1161/strokeaha.118.022155.

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Background and Purpose— Heme and iron are considered to be key factors responsible for secondary insults after intracerebral hemorrhage (ICH). Our previous study showed that LRP1 (low-density lipoprotein receptor–related protein-1)–Hx (hemopexin) facilitates removal of heme. The TLR7 (Toll-like receptor 7)–BTK (Bruton tyrosine kinase)–CRT (calreticulin) pathway regulates the expression of LRP1-Hx. This study is designed to clarify whether TLR7 activation facilitates heme scavenging and to establish the potential role of the BTK-CRT-LRP1-Hx signaling pathway in the pathophysiology of ICH. Methods— ICH was induced by stereotactic, intrastriatal injection of type VII collagenase. Mice received TLR7 agonist (imiquimod) via intraperitoneal injection after ICH induction. TLR7 inhibitor (ODN2088), BTK inhibitor (LFM-A13), and CRT agonist (thapsigargin) were given in different groups to further evaluate the underlying pathway. Mice were randomly divided into sham, ICH+vehicle (normal saline), ICH+Imiquimod (2.5, 5, and 10 μg/g), ICH+ODN2088, ICH+LFM-A13, ICH+thapsigargin, and ICH+ODN2088+thapsigargin. Imiquimod was administered twice daily starting at 6 hours after ICH; ODN2088 was administered by intracerebroventricular injection at 30 minutes, and LFM-A13 or thapsigargin was administered by intraperitoneal injection at 3 hours after ICH induction. Neurological scores, cognitive abilities, as well as brain edema, blood-brain barrier permeability, hemoglobin level, brain expression of TLR7/BTK/CRT/LRP1/Hx were analyzed. Results— Low dosage imiquimod significantly attenuated hematoma volume, brain edema, BBB permeability, and neurological deficits after ICH. Imiquimod also increased protein expressions of TLR7, BTK, CRT, LRP1, and Hx; ODN2088 reduced TLR7, BTK, CRT, LRP1, and Hx expressions. Conclusions— TLR7 plays an important role in heme scavenging after ICH by modulating the BTK-CRT-LRP1-Hx pathway. TLR7 may offer protective effects by promoting heme resolution and reduction of brain edema after ICH.
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Vijayan, Vijith, Eveline Baumgart-Vogt, Srivatsava Naidu, Guofeng Qian, and Stephan Immenschuh. "Bruton's Tyrosine Kinase and Nrf2 mediate TLR-induced activation of Heme oxygenase-1 gene expression in macrophages (116.16)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 116.16. http://dx.doi.org/10.4049/jimmunol.186.supp.116.16.

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Abstract The inducible isoform of heme oxygenase (HO)-1, is involved in heme degradation producing CO and biliverdin, mediating cytoprotection against oxidative stress. Recently, HO-1 has been shown to evoke potent anti-inflammatory and immunomodulatory effects in macrophages. Here we demonstrate that Bruton's tyrosine kinase (Btk), the gene of which is mutated in human immunodeficiency X-linked agammaglobulinemia, is involved in toll-like receptor (TLR)-induced gene expression of HO-1 in macrophages. The Btk inhibitor LFM-A13 blocked the induction of HO-1 by LPS (TLR4 ligand) in RAW264.7 macrophages and primary mouse alveolar macrophages. Furthermore, LPS-stimulated up-regulation of HO-1 gene expression was abrogated in alveolar macrophages from Btk-/- mice. In addition, inhibition of Btk with LFM-A13 attenuated the LPS-induced luciferase activity of the HO-1 promoter in transfection studies in RAW264.7 cells. This effect was mediated by the transcription factor Nrf2, which is a master regulator of the cellular antioxidant defense. Immunofluorescence studies revealed that the nuclear translocation of Nrf2 in LPS-treated macrophages was reduced by Btk inhibition. Moreover, the generation of reactive oxygen species (ROS), but not that of NO, was involved in this regulatory pathway. Btk-dependent induction of HO-1 gene expression via Nrf2 was also observed upon stimulation by TLR7 and TLR9 ligands, suggesting Btk to be generally involved in TLR-mediated HO-1 gene activation.
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Tankiewicz-Kwedlo, Anna, Justyna Magdalena Hermanowicz, Tomasz Domaniewski, Krystyna Pawlak, Małgorzata Rusak, Anna Pryczynicz, Arkadiusz Surazynski, Tomasz Kaminski, Adam Kazberuk, and Dariusz Pawlak. "Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer." British Journal of Pharmacology 175, no. 5 (January 25, 2018): 743–62. http://dx.doi.org/10.1111/bph.14099.

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8

Uckun, Fatih M. "Chemosensitizing Anti-Cancer Activity of LFM-A13, a Leflunomide Metabolite Analog Targeting Polo-like Kinases." Cell Cycle 6, no. 24 (December 15, 2007): 3021–26. http://dx.doi.org/10.4161/cc.6.24.5096.

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Hermanowicz, J. M., A. Tankiewicz-Kwedlo, A. Surażyński, K. Pawlak, and D. A. Pawlak. "Simultaneous use of erythropoietin and LFM-A13 as a new therapeutic approach for colorectal cancer." Annals of Oncology 29 (March 2018): iii17. http://dx.doi.org/10.1093/annonc/mdy047.030.

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Uckun, Fatih M., Ilker Dibirdik, Sanjive Qazi, Alexei Vassilev, Hong Ma, Chen Mao, Alexey Benyumov, and Katayoon H. Emami. "Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)." Bioorganic & Medicinal Chemistry 15, no. 2 (January 2007): 800–814. http://dx.doi.org/10.1016/j.bmc.2006.10.050.

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Dissertations / Theses on the topic "LFM-A13"

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NARLOCH, ROBERT. "Characterization of a novel isoform of Bruton's Tyrosine Kinase (BTK) involved in resistance to drug-induced apoptosis of carcinoma cells." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2010. http://hdl.handle.net/10281/10304.

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Cancer is a multistep process in which mutation of 4 to 6 genes has to occur for the cell to become fully oncogenic. Very often, genes affected by such mutations encode for molecules belonging to the pathways allowing DNA repair or controlling the apoptotic process. Many anticancer drugs act by inducing DNA damage, which in turn triggers apoptosis. Inability of tumour cells to undergo chemotherapy-induced apoptosis is a main mechanism of drug resistance. Therefore, in order to find rational targets to tailor therapy is necessary to identify novel genes involved in modulating apoptosis induced by chemotherapeutics. Recently in our lab a loss-of-function RNAi-library-based phenotypic screen has been performed which identified 49 novel genes whose silencing reverts 5-fluoraouracil (FU) resistance in a model colon cancer cell line (HCT116p5KO). The aim of the project was to study the role of one of the targets identified in the abovementioned screen, the Bruton’s tyrosine kinase (BTK), so far assumed to be expressed only in hematopoietic lineages. Our findings suggest that BTK could be an interesting candidate to be targeted in the therapy of drug-resistant colon cancers and a marker of drug-resistance.
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