1. Apoptosis is induced in cancer cells via the mitochondrial pathway by the novel xylocydine-derived compound JRS-15.
- Author
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Sun C, Guo XX, Zhu D, Xiao C, Bai X, Li Y, Zhan Z, Li XL, Song ZG, and Jin YH
- Subjects
- Caspases metabolism, Cell Cycle Checkpoints drug effects, Cell Line, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cyclin-Dependent Kinases antagonists & inhibitors, Dose-Response Relationship, Drug, Enzyme Inhibitors chemistry, HeLa Cells, Hep G2 Cells, Humans, Immunoblotting, Membrane Potential, Mitochondrial drug effects, Mitochondria metabolism, Mitochondria physiology, Molecular Structure, Neoplasms metabolism, Neoplasms pathology, Nucleosides chemistry, Poly(ADP-ribose) Polymerases metabolism, X-Linked Inhibitor of Apoptosis Protein metabolism, bcl-X Protein metabolism, Apoptosis drug effects, Enzyme Inhibitors pharmacology, Mitochondria drug effects, Nucleosides pharmacology, Signal Transduction drug effects
- Abstract
The novel compound JRS-15 was obtained through the chemical modification of xylocydine. JRS-15 exhibited much stronger cytotoxic and pro-apoptotic activity than its parent compound in various cancer cell lines, with IC(50) values in HeLa, HepG2, SK-HEP-1, PC-3M and A549 cells ranging from 12.42 to 28.25 µM. In addition, it is more potent for killing cancer than non-cancerous cells. Mechanistic studies showed that JRS-15 treatment arrested cell cycle at the G1/S phase, which further triggered the translocation of Bax and Bak to the mitochondria, resulting in mitochondrial membrane potential (MMP) depolarization and the subsequent release of cytochrome c and the second mitochondria-derived activator of caspase (Smac). The sequential activation of caspase-9 and caspase-3/7 and the cleavage of poly (ADP-ribose) polymerase (PARP) were observed following these mitochondrial events. Caspase-8, an initiator caspase that is required to activate the membrane receptor-mediated extrinsic apoptosis pathway was not activated in JRS-15-treated cells. Further analysis showed that the levels of the anti-apoptotic proteins Bcl-xL and XIAP were significantly reduced upon JRS-15 treatment. Furthermore, the caspase-9 inhibitor z-LEHD-fmk, the pan-caspase inhibitor z-VAD-fmk, and Bcl-xL or XIAP overexpression all effectively prevented JRS-15-induced apoptosis. Taken together, these results indicate that JRS-15 induces cancer cell apoptosis by regulating multiple apoptosis-related proteins, and this compound may therefore be a good candidate reagent for anticancer therapy.
- Published
- 2013
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