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

Journal Article · Tue Mar 01 04:00:00 EST 2011 · Toxicology and Applied Pharmacology

OSTI ID:21535247

Xia, Li ^[1]; Wu, William K.K. ^[2]; Bin, Sun ^[1]; Min, Cui; Shanshan, Liu ^[3]; Jian, Gao ^[1]

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1. School of Pharmaceutical Sciences, Shandong University, Jinan 250012 (China)
2. Institute of Digestive Diseases, LKS Institute of Health Sciences and Department of Medicine and Therapeutics, Chinese University of Hong Kong (Hong Kong)
3. School of Ocean, Shandong University, Weihai 264209 (China)

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{sub 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{sup 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{sub 1}, a cyclin required for progression through the G{sub 2}/M phase. Taken together, DHA induces G{sub 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.

• OSTI ID: 21535247
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Journal Issue: 2 Vol. 251; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CELL CYCLE
CHEMICAL REACTIONS
DISEASES
DRUGS
GENES
HUMAN POPULATIONS
NEOPLASMS
OSTEOSARCOMAS
PHOSPHORYLATION
POPULATIONS
SARCOMAS
SKELETAL DISEASES
STIMULATION