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




Apoptosis is Induced in Cancer Cells via the Mitochondrial Pathway by the Novel Xylocydine-Derived Compound JRS-15 - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

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.



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. 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





Autor: 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,*

Fuente: http://mdpi.com/



DESCARGAR PDF




Documentos relacionados