期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 192, 期 -, 页码 -出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2020.112158
关键词
Microtubule-targeting agents; Drug-resistant cancer cells; Histone deacetylases (HDAC)
资金
- Ministry of Science and Technology, Taiwan [MOST 106-2113-M-038 -002, 1072113-M-038 -001, 108-2320-B-038-056]
Microtubule-targeting agents (MTA) have enjoyed significant clinical success for decades. However, several mechanisms may cause inactivation of such drugs, leading to acquired resistance in patients treated with them. Therefore, drugs containing a stilbene-like skeleton and possessing dual inhibitory activity may provide a new and differentiated treatment for patients to overcome challenging acquired resistance. A new compound (16c) displays promising anticancer activity with GI(50) of 22 +/- 2 and 12 +/- 0.1 nM in vincristine-resistant nasopharyngeal (KB-Vin) cancer cells and etoposide-resistant nasopharyngeal (KB-7D) cancer cells and is better than vincristine, etoposide, ABT-751, and MS-275. A mechanistic study revealed that 16c interferes with the cell cycle distribution and induces cell cycle arrest at the G2/M phase and severe mitotic spindle defects followed by apoptosis. In addition, it produces much more significant cytotoxicity than vincristine and etoposide in the corresponding resistant cells, indicating that it may be a promising candidate to overcome drug resistance in cancer cells. Compound 16c also displays inhibitory activity against HDAC 1 and HDAC 2 with IC50 values of 1.07 mu M, and 1.47 mu M, respectively. These findings may lead to a new type of structural motif for future development of drugs that could overcome acquired resistance to MTAs. (c) 2020 Published by Elsevier Masson SAS.
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