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Dihydroptychantol A, a macrocyclic bisbibenzyl derivative, induces autophagy and following apoptosis associated with p53 pathway in human osteosarcoma U2OS cells.
MedLine Citation:
PMID:  21185854     Owner:  NLM     Status:  Publisher    
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 G(2)/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-meditated 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 B(1), a cyclin required for progression through the G(2)/M phase. Taken together, DHA induces G(2)/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.
Xia Li; William K K Wu; Bin Sun; Min Cui; Shanshan Liu; Jian Gao; Hongxiang Lou
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2010-12-24
Journal Detail:
Title:  Toxicology and applied pharmacology     Volume:  -     ISSN:  1096-0333     ISO Abbreviation:  -     Publication Date:  2010 Dec 
Date Detail:
Created Date:  2011-1-12     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0416575     Medline TA:  Toxicol Appl Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2010 Elsevier Inc. All rights reserved.
School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China; School of Ocean, Shandong University, Weihai 264209, China.
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