Pterostilbene induces autophagy and apoptosis in sensitive and chemoresistant human bladder cancer cells.
METHODS
Bladder cancer is one of the most common malignancies in the world. The majority of bladder cancer deaths are due to unresectable lesions that are resistant to chemotherapy. Pterostilbene (PT), a naturally occurring phytoalexin, possesses a variety of pharmacologic activities, including antioxidant, cancer prevention activity and cytotoxicity to many cancers. We found that PT effectively inhibits the growth of sensitive and chemoresistant human bladder cancer cells by inducing cell cycle arrest, autophagy and apoptosis. Down-regulations of Cyclin A, B and D1 and pRB are the results of PT-induced cell cycle arrest.


RESULTS
Autophagy occurred at an early stage and was observed through the formation of acidic vesicular organelles (the marker for autophagy) and microtubule-associated protein 1 light chain 3-II production. Apoptosis occurred at a later stage and was detected by Annexin V and 4',6-diamidino-2-phenylindole staining. PT-induced autophagy was triggered by the inhibition of active human protein kinase/the mammalian TOR/p70S6K pathway and activation of extracellular signal-regulated kinase pathway. Inhibition of autophagy by pretreatment with 3-methyladenine, bafilomycin A1, Beclin 1 or extracellular signal-regulated kinase short hairpin RNA enhanced PT-triggered apoptosis.


CONCLUSIONS
This is the first study to demonstrate that PT causes autophagy in cancer cells and suggests that PT could serve as a new and promising agent for the treatment of sensitive and chemoresistant bladder cancer cells.
Chen
Rong-Jane
RJ
Department of Environmental and Occupational Health, National Cheng Kung University Medical College, Tainan, Taiwan.
Ho
Chi-Tang
CT
Wang
Ying-Jan
YJ
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D015398:Signal Transduction; D013267:Stilbenes / Q000494:pharmacology*; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000473:pathology*
D008869:Microtubule-Associated Proteins; D013267:Stilbenes; C107773:pterostilbene; C025946:3-methyladenine; D020928:Mitogen-Activated Protein Kinases; D000225:Adenine