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Int. J. Mol. Sci. 2013, 14(1), 850-870; doi:10.3390/ijms14010850

Article

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

Chao Sun ¹ , Xiao-Xi Guo ¹ , Dan Zhu ¹ , Chuan Xiao ² , Xiao Bai ³ , Yang Li ¹ , Zhuo Zhan ¹ , Xiang-Long Li ¹ , Zhi-Guang Song ^2,*  and Ying-Hua Jin ^1,*

¹ Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, College of Life Science, Jilin University, Changchun 130012, China ² College of Chemistry, Jilin University, Changchun 130021, China ³ Norman Bethune College of Medicine, Jilin University, Changchun 130021, China

* Authors to whom correspondence should be addressed.

Received: 24 October 2012; in revised form: 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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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 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.

Keywords: apoptosis; Bax; Bak; Bcl-xL; cell cycle; cytochrome c; JRS-15; Smac; XIAP

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