Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells
| العنوان: | Circumvention of Mcl-1-dependent drug resistance by simultaneous Chk1 and MEK1/2 inhibition in human multiple myeloma cells |
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| المؤلفون: | Liang Zhou, Wesley W. Bodie, Jessica Felthousen, Robert Z. Orlowski, Shuang Chen, Xin Yan Pei, Lora Kramer, Michael W. Sanderson, Leena E. Youssefian, Yun Dai, Steven Grant, Yukie Takabatake |
| المصدر: | PLoS ONE PLoS ONE, Vol 9, Iss 3, p e89064 (2014) |
| سنة النشر: | 2013 |
| مصطلحات موضوعية: | Cancer Treatment, lcsh:Medicine, Apoptosis, Drug resistance, Signal transduction, ERK signaling cascade, Plasma Cell Disorders, Syndecan 1, Bortezomib, Hematologic Cancers and Related Disorders, 0302 clinical medicine, Molecular cell biology, immune system diseases, hemic and lymphatic diseases, Signaling in Cellular Processes, lcsh:Science, Crosstalk, bcl-2-Associated X Protein, Apoptotic Signaling, 0303 health sciences, Multidisciplinary, biology, Bcl-2-Like Protein 11, Cell Death, Chemistry, Mechanisms of Signal Transduction, Signaling cascades, Antiapoptotic Signaling, Hematology, Boronic Acids, Cell biology, Up-Regulation, Haematopoiesis, bcl-2 Homologous Antagonist-Killer Protein, Oncology, 030220 oncology & carcinogenesis, Pyrazines, Benzamides, Intercellular Signaling Peptides and Proteins, Medicine, biological phenomena, cell phenomena, and immunity, Multiple Myeloma, Bcl-2 Homologous Antagonist-Killer Protein, medicine.drug, Protein Binding, Research Article, Stromal cell, MAPK signaling cascades, Down-Regulation, Signaling Pathways, Cell Growth, 03 medical and health sciences, Bcl-2-associated X protein, Apoptotic signaling cascade, Cell Line, Tumor, Proto-Oncogene Proteins, medicine, Cell Adhesion, Humans, Myelomas and Lymphoproliferative Diseases, neoplasms, Protein Kinase Inhibitors, Biology, 030304 developmental biology, Mitogen-Activated Protein Kinase Kinases, lcsh:R, Mesenchymal stem cell, Membrane Proteins, Cancers and Neoplasms, Mesenchymal Stem Cells, Chemotherapy and Drug Treatment, Cytoprotection, Drug Resistance, Neoplasm, Checkpoint Kinase 1, biology.protein, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, lcsh:Q, Syndecan-1, Apoptosis Regulatory Proteins, Protein Kinases |
| الوصف: | The anti-apoptotic protein Mcl-1 plays a major role in multiple myeloma (MM) cell survival as well as bortezomib- and microenvironmental forms of drug resistance in this disease. Consequently, there is a critical need for strategies capable of targeting Mcl-1-dependent drug resistance in MM. The present results indicate that a regimen combining Chk1 with MEK1/2 inhibitors effectively kills cells displaying multiple forms of drug resistance stemming from Mcl-1 up-regulation in association with direct transcriptional Mcl-1 down-regulation and indirect disabling of Mcl-1 anti-apoptotic function through Bim up-regulation and increased Bim/Mcl-1 binding. These actions release Bak from Mcl-1, accompanied by Bak/Bax activation. Analogous events were observed in both drug-naïve and acquired bortezomib-resistant MM cells displaying increased Mcl-1 but diminished Bim expression, or cells ectopically expressing Mcl-1. Moreover, concomitant Chk1 and MEK1/2 inhibition blocked Mcl-1 up-regulation induced by IL-6/IGF-1 or co-culture with stromal cells, effectively overcoming microenvironment-related drug resistance. Finally, this regimen down-regulated Mcl-1 and robustly killed primary CD138+ MM cells, but not normal hematopoietic cells. Together, these findings provide novel evidence that this targeted combination strategy could be effective in the setting of multiple forms of Mcl-1-related drug resistance in MM. |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::aecf1022ca785e509cda664737c0b904Test https://pubmed.ncbi.nlm.nih.gov/24594907Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....aecf1022ca785e509cda664737c0b904 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
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