Tetrandrine induces apoptosis by activating reactive oxygen species and repressing Akt activity in human hepatocellular carcinoma.

Abstract

Tetrandrine, a bisbenzylisoquinoline alkaloid component of broadly used traditional Chinese medicine, has antitumor effects against some cancers. In our study, we investigated the effects of tetrandrine on the human hepatocellular carcinoma (HCC) in vitro and in vivo. The results showed that tetrandrine effectively induced apoptosis of liver cancer cell in a dose- and time-dependent manner accompanied by alteration of cell morphology, chromatin fragmentation and caspase activation. Tetrandrine treatment also induced intracellular accumulation of reactive oxygen species (ROS), and ROS scavengers (LNAC and GSH) completely blocked the effects of tetrandrine-induced apoptosis, suggesting that the generation of ROS plays an important role in tetrandrine-induced apoptosis. Although the activities of JNK and ERK were inhibited significantly by tetrandrine treatment, JNK and ERK are not involved in the tetrandrine-induced apoptosis. In contrast, Akt activity was found to be closely related to tetrandrine-induced apoptosis. The data demonstrated that Akt activity inhibitor LY294002 synergistically promoted tetrandrine-induced apoptosis of HCC, whereas ectopic expression of Akt contrastly abrogated partial of the tetrandrine-induced apoptosis. These data suggest that Akt signal is the downstream event of ROS generation in the tetrandrine-induced HCC cell apoptosis. Moreover, the results of xenograft in nude mice were consistent with that of the in vitro studies. Therefore, our data suggest that tetrandrine may be a promising agent for the treatment of HCC as a regulator of ROS/Akt pathway.

• Authors: Chaoyang Liu, Ke Gong, Xin Mao, Wenhua Li
• Journal: International journal of cancer (Int J Cancer) Vol. 129 Issue 6 Pg. 1519-31 (Sep 15 2011) ISSN: 1097-0215 [Electronic] United States
• PMID: 21128229 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 UICC.

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzylisoquinolines
• Drugs, Chinese Herbal
• Reactive Oxygen Species
• tetrandrine
• Proto-Oncogene Proteins c-akt
• Caspases

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Benzylisoquinolines (pharmacology)
• Carcinoma, Hepatocellular (drug therapy, metabolism, pathology)
• Caspases (biosynthesis)
• Cell Line, Tumor
• Dose-Response Relationship, Drug
• Drugs, Chinese Herbal (pharmacology)
• Enzyme Activation (drug effects)
• Humans
• Liver Neoplasms (drug therapy, metabolism, pathology)
• Male
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-akt (metabolism)
• Reactive Oxygen Species (metabolism)
• Xenograft Model Antitumor Assays