title: 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.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.forename: William K K
authors.initials: WK
authors.lastname: Wu
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Min
authors.initials: M
authors.lastname: Cui
authors.forename: Shanshan
authors.initials: S
authors.lastname: Liu
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Hongxiang
authors.initials: H
authors.lastname: Lou
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D001632:Bibenzyls / Q000633:toxicity; D045744:Cell Line, Tumor; D006801:Humans; D047028:Macrocyclic Compounds / Q000633:toxicity; D012516:Osteosarcoma / Q000378:metabolism / Q000473:pathology; D010647:Phenyl Ethers / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D013267:Stilbenes / Q000633:toxicity*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D001632:Bibenzyls; D047028:Macrocyclic Compounds; D010647:Phenyl Ethers; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; C539241:dihydroptychantol A