Apoptosis is induced in cancer cells via the mitochondrial pathway by the novel xylocydine-derived compound JRS-15.
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.
Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education,  College of Life Science, Jilin University, Changchun 130012, China. szg@jlu.edu.cn.
Chao
C
Sun
Xiao-Xi
XX
Guo
Dan
D
Zhu
Chuan
C
Xiao
Xiao
X
Bai
Yang
Y
Li
Zhuo
Z
Zhan
Xiang-Long
XL
Li
Zhi-Guang
ZG
Song
Ying-Hua
YH
Jin
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D015151:Immunoblotting; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015394:Molecular Structure; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C000601356:4-amino-6-(3-(3-bromophenyl)phenyl)-7-(xylofuranosyl)pyrolo(2,3-d)pyrimidine-5-nitrile; C547380:4-amino-6-bromo-7-(xylofuranosyl)pyrrolo(2,3-d)pyrimidine-5-carboxamide; D004791:Enzyme Inhibitors; D009705:Nucleosides; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D051020:bcl-X Protein; D011065:Poly(ADP-ribose) Polymerases; D018844:Cyclin-Dependent Kinases; D020169:Caspases