title: Oxymatrine synergistically enhances the inhibitory effect of 5-fluorouracil on hepatocellular carcinoma in vitro and in vivo.
abstract: Oxymatrine (OMT), one of the main active components of extracts from the dry roots of Sophora flavescens, has long been employed clinically to treat cancers. Here, we investigated the synergistic effect of OMT with 5-fluorouracil (5-Fu) on the tumor growth inhibition of hepatocellular carcinoma cells (HCC; Hep-G2 and SMMC-7721) and explored the underlying mechanism. Cells were treated with OMT and/or 5-Fu and subjected to cell viability, colony formation, apoptosis, cell cycle, western blotting, xenograft tumorigenicity assay, and immunohistochemistry. OMT and 5-Fu inhibited the proliferation of Hep-G2 and SMMC-7721 cells, and combination treatment with OMT and 5-Fu resulted in a combination index <1, indicating a synergistic effect. Co-treatment with OMT and 5-Fu caused G0/G1 phase arrest by upregulating P21 and P27 and downregulating cyclin D, and induced apoptosis through increasing the production of reactive oxygen species (ROS) and decreasing the levels of p-ERK. In addition, the inhibition of ROS respectively reversed the cell death induced by 5-Fu + OMT, suggesting the key roles of ROS in the process. More importantly, 5-Fu and OMT in combination exhibit much superior tumor weight and volume inhibition on SMMC-7721 xenograft mouse model in comparison to 5-Fu or OMT alone. Immunohistochemistry analysis suggests the combinations greatly suppressed tumor proliferation, which was consistent with our in vitro results. Taken together, our findings indicated that OMT sensitizes HCC to 5-Fu treatment by the suppression of ERK activation through the overproduction of ROS, and combination treatment with OMT and 5-Fu would be a promising therapeutic strategy for HCC treatment.
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Geriatric Ward, Wujiang No. 1 People's Hospital, Suzhou, 215200, China.
authors.forename: Tingting
authors.initials: T
authors.lastname: Bi
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Dai
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China.
authors.forename: Liqiang
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China. wjyygqgg@sohu.com.
authors.forename: Quangen
authors.initials: Q
authors.lastname: Gao
authors.affiliation: Department of General Surgery, Wujiang No. 1 People's Hospital, Suzhou, 215200, China. wjyysgh@163.com.
authors.forename: Genhai
authors.initials: G
authors.lastname: Shen
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D011807:Quinolizines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000964:Antimetabolites, Antineoplastic; D000998:Antiviral Agents; D005472:Fluorouracil; D011807:Quinolizines; D017382:Reactive Oxygen Species; C037573:oxymatrine; D000093842:Matrines
keywords: 5-Fluorouracil; Hepatocellular carcinoma; Oxymatrine; ROS