Identification of an annonaceous acetogenin mimetic, AA005, as an AMPK activator and autophagy inducer in colon cancer cells.

Abstract

Annonaceous acetogenins, a large family of naturally occurring polyketides isolated from various species of the plant genus Annonaceae, have been found to exhibit significant cytotoxicity against a variety of cancer cells. Previous studies showed that these compounds could act on the mitochondria complex-I and block the corresponding electron transport chain and terminate ATP production. However, more details of the mechanisms of action remain ambiguous. In this study we tested the effects of a set of mimetics of annonaceous acetogenin on some cancer cell lines, and report that among them AA005 exhibits the most potent antitumor activity. AA005 depletes ATP, activates AMP-activated protein kinase (AMPK) and inhibits mTOR complex 1 (mTORC1) signal pathway, leading to growth inhibition and autophagy of colon cancer cells. AMPK inhibitors compound C and inosine repress, while AMPK activator AICAR enhances, AA005-caused proliferation suppression and subsequent autophagy of colon cancer cells. AA005 enhances the ATP depletion and AMPK activation caused by 2-deoxyglucose, an inhibitor of mitochondrial respiration and glycolysis. AA005 also inhibits chemotherapeutic agent cisplatin-triggered up-regulation of mTOR and synergizes with this drug in suppression of proliferation and induction of apoptosis of colon cancer cells. These data indicate that AA005 is a new metabolic inhibitor which exhibits therapeutic potentials in colon cancer.

• Authors: Yong-Qiang Liu, Xin Cheng, Liang-Xia Guo, Chan Mao, Yi-Jie Chen, Hai-Xia Liu, Qi-Cai Xiao, Sheng Jiang, Zhu-Jun Yao, Guang-Biao Zhou
• Journal: PloS one (PLoS One) Vol. 7 Issue 10 Pg. e47049 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23056575 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• AA005
• Acetogenins
• Fatty Alcohols
• Lactones
• Pyrazoles
• Pyrimidines
• dorsomorphin
• Adenosine Triphosphate
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Acetogenins (chemistry)
• Adenosine Triphosphate (metabolism)
• Autophagy (drug effects)
• Cell Line
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Fatty Alcohols (chemistry, pharmacology)
• Humans
• Lactones (chemistry, pharmacology)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)