Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15
AbstractThe 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 IC50 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.
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Sun, C.; Guo, X.-X.; Zhu, D.; Xiao, C.; Bai, X.; Li, Y.; Zhan, Z.; Li, X.-L.; Song, Z.-G.; Jin, Y.-H. Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15. Int. J. Mol. Sci. 2013, 14, 850-870.
Sun C, Guo X-X, Zhu D, Xiao C, Bai X, Li Y, Zhan Z, Li X-L, Song Z-G, Jin Y-H. Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15. International Journal of Molecular Sciences. 2013; 14(1):850-870.Chicago/Turabian Style
Sun, Chao; Guo, Xiao-Xi; Zhu, Dan; Xiao, Chuan; Bai, Xiao; Li, Yang; Zhan, Zhuo; Li, Xiang-Long; Song, Zhi-Guang; Jin, Ying-Hua. 2013. "Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15." Int. J. Mol. Sci. 14, no. 1: 850-870.