18beta-Glycyrrhetinic acid induces apoptotic cell death in SiHa cells and exhibits a synergistic effect against antibiotic anti-cancer drug toxicity.
Defects in mitochondrial function have been shown to participate in the induction of cell death in cancer cells. The present study was designed to assess the toxic effect of 18beta-glycyrrhetinic acid against human cervix and uterus tumor cell line SiHa cells in relation to the mitochondria-mediated cell-death process and evaluate the combined toxic effect of 18beta-glycyrrhetinic acid and anti-cancer drugs. 18beta-Glycyrrhetinic acid induced the nuclear damage, changes in the mitochondrial membrane permeability, formation of reactive oxygen species and depletion of glutathione in SiHa cells. It caused cell death by inducing the increase in the pro-apoptotic Bax protein and cytochrome c levels, reduction in anti-apoptotic Bcl-2 level, subsequent caspase-3 activation and loss of the mitochondrial transmembrane potential. Unlike 18beta-glycyrrhetinic acid, a pro-compound glycyrrhizin up to 100 microM did not induce cell death and depletion of glutathione. Combined treatment of mitomycin c (or doxorubicin) and 18beta-glycyrrhetinic acid revealed a synergistic toxic effect. Meanwhile, combination of camptothecin and 18beta-glycyrrhetinic acid exhibited an additive cytotoxic effect. Results suggest that 18beta-glycyrrhetinic acid may cause cell death in SiHa cells by inducing the mitochondrial membrane permeability change, leading to cytochrome c release and caspase-3 activation. The effect may be associated with increased formation of reactive oxygen species and depletion of glutathione. Combined treatment of antibiotic anti-cancer drug and 18beta-glycyrrhetinic acid seems to exhibit a synergistic toxic effect.
Lee
Chung Soo
CS
Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, South Korea. leecs@cau.ac.kr
Kim
Yun Jeong
YJ
Lee
Min Sung
MS
Han
Eun Sook
ES
Lee
Sun Joo
SJ
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D005978:Glutathione / Q000378:metabolism; D006034:Glycyrrhetinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D051336:Mitochondrial Membranes / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D004338:Drug Combinations; D017382:Reactive Oxygen Species; C119129:18alpha-glycyrrhetinic acid; D005978:Glutathione; D006034:Glycyrrhetinic Acid