A phenylphthalimide derivative, TC11, induces apoptosis by degrading MCL1 in multiple myeloma cells
| Autor: | Yutaka Hattori, Maiko Matsushita, Wakana Murota, Daiju Ichikawa, Sho Osawa, Misa Nakamura, Hiroshi Yanagawa |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Cell Survival Biophysics Antineoplastic Agents Apoptosis Phthalimides Biochemistry Structure-Activity Relationship 03 medical and health sciences 0302 clinical medicine Tumor Cells Cultured medicine Humans Immunologic Factors MCL1 Molecular Biology Multiple myeloma Lenalidomide Cyclin-dependent kinase 1 Dose-Response Relationship Drug Chemistry Cereblon Cell Cycle Cell Biology medicine.disease Chromosome 17 (human) 030104 developmental biology Mechanism of action 030220 oncology & carcinogenesis Cancer research Myeloid Cell Leukemia Sequence 1 Protein Drug Screening Assays Antitumor medicine.symptom Multiple Myeloma medicine.drug |
| Zdroj: | Biochemical and Biophysical Research Communications. 521:252-258 |
| ISSN: | 0006-291X |
| DOI: | 10.1016/j.bbrc.2019.10.119 |
| Popis: | To date, the prognosis of multiple myeloma (MM) in patients harboring cytogenetic abnormalities (CA) involving t (4; 14) and deletion of chromosome 17 remains poor despite recent advances in drug development that include the use of immunomodulatory drugs (IMiDs) such as lenalidomide for MM. To address this issue, we have developed a novel phenylphthalimide derivative, TC11, that is structurally related to IMiDs. It remains unclear how TC11 induces apoptosis of MM cells with high-risk CA. Here, we show that TC11 does not induce degradation of CRBN's substrates, IKZF1/3 and CK1α, and induces apoptosis of CRBN-silenced MM; this effect was independent of the cereblon (CRBN) pathway, which is involved in the mechanism of action of IMiDs used for the treatment of MM. We also revealed that TC11, in contrast to existing IMiDs, induced degradation of MCL1 and activation of caspase-9. Furthermore, inhibition of CDK1 by CGP74514A prevented TC11-induced MCL1 degradation, caspase-9 activation, and the subsequent apoptotic cell death. We showed that ectopic MCL1 expression rescued apoptosis of MM. These observations suggest that TC11 induces apoptotic death caused by degradation of MCL1 during prolonged mitotic arrest. Therefore, our findings suggest that TC11 is a potential drug candidate for high-risk MM. |
| Databáze: | OpenAIRE |
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