Dihydroptychantol A, a macrocyclic bisbibenzyl derivative, induces autophagy and following apoptosis associated with p53 pathway in human osteosarcoma U2OS cells.

Abstract

Dihydroptychantol A (DHA), a novel macrocyclic bisbibenzyl compound extracted from liverwort Asterella angusta, has antifungal and multi-drug resistance reversal properties. Here, the chemically synthesized DHA was employed to test its anti-cancer activities in human osteosarcoma U2OS cells. Our results demonstrated that DHA induced autophagy followed by apoptotic cell death accompanied with G₂/M-phase cell cycle arrest in U2OS cells. DHA-induced autophagy was morphologically characterized by the formation of double membrane-bound autophagic vacuoles recognizable at the ultrastructural level. DHA also increased the levels of LC3-II, a marker of autophagy. Surprisingly, DHA-mediated apoptotic cell death was potentiated by the autophagy inhibitor 3-methyladenine, suggesting that autophagy may play a protective role that impedes the eventual cell death. Furthermore, p53 was shown to be involved in DHA-mediated autophagy and apoptosis. In this connection, DHA increased nuclear expression of p53, induced p53 phosphorylation, and upregulated p53 target gene p21(Waf1/Cip1). In contrast, cytoplasmic p53 was reduced by DHA, which contributed to the stimulation of autophagy. In relation to the cell cycle, DHA decreased the expression of cyclin B₁, a cyclin required for progression through the G₂/M phase. Taken together, DHA induces G₂/M-phase cell cycle arrest and apoptosis in U2OS cells. DHA-induced apoptosis was preceded by the induction of protective autophagy. DHA-mediated autophagy and apoptosis are associated with the cytoplasmic and nuclear functions of p53.

• Authors: Xia Li, William K K Wu, Bin Sun, Min Cui, Shanshan Liu, Jian Gao, Hongxiang Lou
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 251 Issue 2 Pg. 146-54 (Mar 01 2011) ISSN: 1096-0333 [Electronic] United States
• PMID: 21185854 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Bibenzyls
• Macrocyclic Compounds
• Phenyl Ethers
• Stilbenes
• Tumor Suppressor Protein p53
• dihydroptychantol A

Topics

• Apoptosis (drug effects, physiology)
• Autophagy (drug effects, physiology)
• Bibenzyls (toxicity)
• Cell Line, Tumor
• Humans
• Macrocyclic Compounds (toxicity)
• Osteosarcoma (metabolism, pathology)
• Phenyl Ethers (toxicity)
• Signal Transduction (drug effects, physiology)
• Stilbenes (toxicity)
• Tumor Suppressor Protein p53 (physiology)