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Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15

Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China
College of Chemistry, Jilin University, Changchun 130021, China
Norman Bethune College of Medicine, Jilin University, Changchun 130021, China
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2013, 14(1), 850-870;
Received: 24 October 2012 / Revised: 17 December 2012 / Accepted: 21 December 2012 / Published: 4 January 2013
(This article belongs to the Special Issue Signalling Molecules and Signal Transduction in Cells)
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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 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. View Full-Text
Keywords: apoptosis; Bax; Bak; Bcl-xL; cell cycle; cytochrome c; JRS-15; Smac; XIAP apoptosis; Bax; Bak; Bcl-xL; cell cycle; cytochrome c; JRS-15; Smac; XIAP
This is an open access article distributed under the Creative Commons Attribution License (CC BY 3.0).

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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.

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