title: Protection of betulin against cadmium-induced apoptosis in hepatoma cells.
abstract: The protective effects of betulin (BT) against cadmium (Cd)-induced cytotoxicity have been previously reported. However, the mechanisms responsible for these protective effects are unclear. Therefore, this study investigated the mechanisms responsible for the protection of BT against Cd-induced cytotoxicity in human hepatoma cell lines. The protection of BT against Cd cytotoxicity was more effective in the HepG2 than in the Hep3B cells. The protection of BT on Cd-induced cytotoxicity in the HepG2 cells appeared to be related to the inhibition of apoptosis, as determined by PI staining and DNA fragmentation analysis. The anti-apoptosis exerted by BT involved the blocking of Cd-induced reactive oxygen species (ROS) generation, the abrogation of the Cd-induced Fas upregulation, the blocking of caspase-8-dependent Bid activation, and subsequent inhibition of mitochondrial pathway. The BT pretreatment did not affect the p21 and p53 expression levels, when compared with those of the treated cells with Cd alone. BT induced the transient S phase arrest at an early stage and the G0/G1 arrest at a relatively late stage, but it did not observe the sub-G1 apoptotic peak. In the Hep3B cells, Cd did not induce ROS generation. The BT pretreatment partially inhibited the Cd-induced apoptosis, which was related with the incomplete blockage in caspase-9 or -3 activation, as well as in Bax activation. Taken together, it was found that Cd can induce apoptosis via the Fas-dependent and -independent apoptosis pathways. However, the observed protective effects of BT were clearly more sensitive to Fas-expressing HepG2 cells than to Fas-deficient Hep3B cells.
authors.affiliation: Research Center for Resistant Cells, College of Medicine, Chosun University, Dong-gu, Gwangju 501-759, Republic of Korea.
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Choi
authors.forename: Sung-Chul
authors.initials: SC
authors.lastname: Lim
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002104:Cadmium / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8; D020169:Caspases / Q000096:biosynthesis; D002458:Cell Fractionation; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D053938:DNA Fragmentation; D004273:DNA, Neoplasm / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D015854:Up-Regulation; D019014:fas Receptor / Q000187:drug effects / Q000378:metabolism; D000094062:Betulinic Acid
chemical_list: D002104:Cadmium; D053181:Caspase 8; D020169:Caspases; D004273:DNA, Neoplasm; D017382:Reactive Oxygen Species; D014315:Triterpenes; D019014:fas Receptor; C002503:betulin; D000094062:Betulinic Acid; C505530:CASP8 protein, human