Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia
| العنوان: | Inhibition of CDK9 by voruciclib synergistically enhances cell death induced by the Bcl-2 selective inhibitor venetoclax in preclinical models of acute myeloid leukemia |
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| المؤلفون: | Hai Lin, Jun Ma, Jeffrey W. Taub, Yubin Ge, Daniel A. Luedtke, Kathryn White, Xinyu Li, Sijana H. Dzinic, Yongwei Su, Lisa Polin, Juiwanna Kushner, Holly Edwards, Steven Buck |
| المصدر: | Signal Transduction and Targeted Therapy Signal Transduction and Targeted Therapy, Vol 5, Iss 1, Pp 1-11 (2020) |
| بيانات النشر: | Nature Publishing Group UK, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Male, Cancer Research, Chronic lymphocytic leukemia, lcsh:Medicine, Apoptosis, chemistry.chemical_compound, Mice, 0302 clinical medicine, hemic and lymphatic diseases, Medicine, lcsh:QH301-705.5, Sulfonamides, Cell Death, Myeloid leukemia, Middle Aged, 3. Good health, Leukemia, Myeloid, Acute, Proto-Oncogene Proteins c-bcl-2, 030220 oncology & carcinogenesis, Heterografts, Female, Adult, Programmed cell death, Adolescent, Antineoplastic Agents, Drug development, Article, Proto-Oncogene Proteins c-myc, 03 medical and health sciences, Young Adult, Downregulation and upregulation, In vivo, Cell Line, Tumor, Genetics, Animals, Humans, Benzopyrans, neoplasms, Haematological cancer, business.industry, Venetoclax, lcsh:R, medicine.disease, Bridged Bicyclo Compounds, Heterocyclic, Cyclin-Dependent Kinase 9, In vitro, 030104 developmental biology, lcsh:Biology (General), chemistry, Cell culture, Imino Furanoses, Cancer research, Myeloid Cell Leukemia Sequence 1 Protein, business |
| الوصف: | Venetoclax, an FDA-approved Bcl-2 selective inhibitor for the treatment of chronic lymphocytic leukemia and acute myeloid leukemia (AML), is tolerated well in elderly patients with AML and has good overall response rates; however, resistance remains a concern. In this study, we show that targeting CDK9 with voruciclib in combination with venetoclax results in synergistic antileukemic activity against AML cell lines and primary patient samples. CDK9 inhibition enhances venetoclax activity through downregulation of Mcl-1 and c-Myc. However, downregulation of Mcl-1 is transient, which necessitates an intermittent treatment schedule to allow for repeated downregulation of Mcl-1. Accordingly, an every other day schedule of the CDK9 inhibitor is effective in vitro and in vivo in enhancing the efficacy of venetoclax. Our preclinical data provide a rationale for an intermittent drug administration schedule for the clinical evaluation of the combination treatment for AML. |
| اللغة: | English |
| تدمد: | 2059-3635 2095-9907 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::9ae39976d658ff4478ed6b551890e1f8Test http://europepmc.org/articles/PMC7042303Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....9ae39976d658ff4478ed6b551890e1f8 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20593635 20959907 |
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