期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 24, 期 12, 页码 -出版社
MDPI
DOI: 10.3390/ijms24129863
关键词
cytotoxicity; drug resistance; P-glycoprotein; apoptosis; intrinsic pathway; ROS; triterpenoids; dihydrobetulin
Multidrug resistance (MDR) is a common occurrence in cancer treatment, where cancer cells become resistant to chemotherapy drugs due to overexpression of ATP-binding cassette efflux transporters, including P-glycoprotein (P-gp). A new semi-synthetic derivative, MK, was found to have the highest cytotoxicity against cancer cells, but it was not identified as a P-gp inhibitor or substrate. Further studies suggest that the cytotoxic effect of MK on cancer cells may be induced through the ROS-mediated mitochondrial pathway.
Multidrug resistance (MDR) is a common phenomenon in clinical oncology, whereby cancer cells become resistant to chemotherapeutic drugs. A common MDR mechanism is the overexpression of ATP-binding cassette efflux transporters in cancer cells, with P-glycoprotein (P-gp) being one of them. New 3,4-seco-lupane triterpenoids, and the products of their intramolecular cyclization with the removed 4,4-gem-dimethyl group, were synthesized by the selective transformations of the A-ring of dihydrobetulin. Among the semi-synthetic derivatives, the MT-assay-enabled methyl ketone 31 (MK), exhibiting the highest cytotoxicity (0.7-16.6 & mu;M) against nine human cancer cell lines, including P-gp overexpressing subclone HBL-100/Dox, is identified. In silico, MK has been classified as a potential P-gp-inhibitor; however, the Rhodamine 123 efflux test, and the combined use of P-gp-inhibitor verapamil with MK in vitro, showed the latter to be neither an inhibitor nor a substrate of P-gp. As the studies have shown, the cytotoxic effect of MK against HBL-100/Dox cells is, arguably, induced through the activation of the ROS-mediated mitochondrial pathway, as evidenced by the positive Annexin V-FITC staining of apoptotic cells, the cell cycle arrest in the G0/G1 phase, mitochondrial dysfunction, cytochrome c release, and the activation of caspase-9 and -3.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据