Tetrandrine cytotoxicity and its dual effect on oxidative stress-induced apoptosis through modulating cellular redox states in Neuro 2a mouse neuroblastoma cells.
Tetrandrine (TET), a plant alkaloid, is known primarily as a non-selective Ca(2+) channel blocker. On the contrary to the cytoprotective effect on ischemia/reperfusion injury, TET has also been reported to cause cytotoxicity. In this study, we wished to understand the apparently disparate effects of this potential drug and thus investigated molecular mechanisms on proliferation and apoptosis and its effect on oxidative stress-induced apoptosis in Neuro 2a mouse neuroblastoma cells. We showed that TET, at high concentrations, induced cell cycle arrest and apoptosis through oxidative stress with following observations. Firstly, 10 microM TET elevated the reactive oxygen species (ROS) level and accordingly depleted glutathione (GSH) content. Secondly, pretreatment with antioxidants (NAC or GSH) protected cells from TET-induced apoptosis. We also demonstrated that treatment with 10 microM TET caused not only induction of p53, p21(waf1), and Bax, but also nuclear translocation of p53 and hypo-phosphorylation of pRb concurrently. Our important finding is that the concentration-dependent dual effect of TET, either inhibiting or promoting cell death induced by H(2)O(2) was observed, probably through regulating redox balance, which was well reflected on the GSH content in each condition. Besides, inhibition of Ca(2+) influx protected cells from H(2)O(2)-induced apoptosis even in the presence of 10 microM TET. Taken together, our data suggest that TET regulation of cellular redox states may play a major role in its dual action of cytotoxicity and cytoprotection.
Jin
Quanri
Q
Department of Biochemistry, School of Medicine, Kyung Hee University, Seoul 130-701, South Korea.
Kang
Chulhun
C
Soh
Yunjo
Y
Sohn
Nak Won
NW
Lee
Juhie
J
Cho
Yong Ho
YH
Baik
Hyung Hwan
HH
Kang
Insug
I
D000470:Alkaloids / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers / Q000633:toxicity*; D002458:Cell Fractionation; D002470:Cell Survival / Q000187:drug effects; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal; D005978:Glutathione / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D051381:Rats; D017382:Reactive Oxygen Species; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000470:Alkaloids; D044182:Benzylisoquinolines; D002121:Calcium Channel Blockers; D004273:DNA, Neoplasm; D004365:Drugs, Chinese Herbal; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C009438:tetrandrine; D005978:Glutathione