title: Tetramethylpyrazine (TMP) exerts antitumor effects by inducing apoptosis and autophagy in hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is one of the most common types of liver cancers with high recurrence rate and mortality rate. Recent studies have indicated that tetramethylpyrazine (TMP), a purified chemical extracted from Ligusticum wallichii Franchat (ChuanXiong), possessed antitumor effects on HCC, but detailed mechanism remains unclear. Our study aims at investigating the antitumor effect of TMP on HCC and its underlying mechanism. We found that TMP inhibited cell proliferation of HepG2 cells in a dose-dependent way, and xenograft tumor models also indicated that high concentrations of TMP administration inhibited tumor growth. Next, flow cytometric analysis and transmission electron microscope images showed that TMP enhanced cell apoptosis in HepG2 cells, and western blot results showed that TMP promoted cleavage of caspase-3 and PARP in vitro and in vivo. We also found that TMP caused autophagy in HCC in vitro and in vivo. In order to examine the role of autophagy in TMP-induced apoptosis, 3-methyladenine (3-MA) was used to block the action of autophagy. Our data showed TMP-induced autophagy might be a pro-apoptosis process in HCC. Furthermore, the results of anti-oxidative enzymes and oxidation-sensitive fluorescent probe 2, 7-dichlorofluorescein diacetate (DCFH-DA) indicated that TMP induced ROS generation and inhibition of ROS diminished the anticancer function of TMP. In conclusion, our studies provide new insights into the mechanisms underlying the antitumor effect of TMP and suggest that TMP can be a novel therapeutic regimen for HCC.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Jiao
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Pharmacy, 401 Military Hospital, Qingdao 266071, China. Electronic address: miaoqing@fmmu.edu.cn.
authors.forename: Qing
authors.initials: Q
authors.lastname: Miao
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Shan
authors.initials: S
authors.lastname: Miao
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Bi
authors.affiliation: Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Song
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Xuanxuan
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Meng
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Yanhua
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Department of Hand Surgery, 401 Military Hospital, Qingdao 266071, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xi'an 710032, China. Electronic address: wangsiw@fmmu.edu.cn.
authors.forename: Siwang
authors.initials: S
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000648:ultrastructure; D008297:Male; D008807:Mice, Inbred BALB C; D046529:Microscopy, Electron, Transmission; D011719:Pyrazines / Q000008:administration & dosage / Q000627:therapeutic use*; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011719:Pyrazines; D017382:Reactive Oxygen Species; C017953:tetramethylpyrazine
keywords: Apoptosis; Autophagy; Hepatocellular carcinoma; Reactive oxygen species (ROS); Tetramethylpyrazine