title: Antihepatocellular Carcinoma Potential of Tetramethylpyrazine Induces Cell Cycle Modulation and Mitochondrial-Dependent Apoptosis: Regulation of p53 Signaling Pathway in HepG2 Cells In Vitro.
abstract: Tetramethylpyrazine (TMP) was originally isolated from a traditional Chinese herbal medicine, Ligusticum chuanxiong In the present study, TMP exhibits potent antitumor activities in vitro. However, the molecular mechanisms remain to be defined. Hence, this study aims to investigate the antiproliferative and apoptotic effects of TMP on HepG2 and elucidate the underlying mechanisms. Analyses using Cell Counting Kit-8 and real-time cell analyzer indicated that TMP significantly inhibited HepG2 cell proliferation. We also observed that TMP induced cell cycle arrest at the G0/G1 checkpoint and apoptosis, using flow cytometry and high-content screening. Furthermore, our results predicted that TMP could directly decrease mitochondrial membrane potential (Δψm), increase the release of cytochrome c, and increase caspase activation, indicating that mitochondrial pathway apoptosis could be the mechanism for TMP within HepG2 cells. Moreover, TMP altered expression of p53 and the Bcl-2/Bax protein ratio, which revealed that TMP induced cell cycle arrest and caspase-dependent mitochondrial apoptosis in HepG2 cells in vitro. These studies provided mechanistic insights into the antitumor properties of TMP, which may be explored as a potential option for treatment of hepatocellular carcinoma.
authors.affiliation: Department of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Bi
authors.affiliation: Changzhou Affiliated Hospital, Nanjing University of Chinese Medicine, Changzhou, China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Yan
authors.affiliation: Department of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China wp2002123@163.com.
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Qian
authors.affiliation: Department of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Qiu
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; C017953:tetramethylpyrazine
keywords: caspase activation; cytochrome c release; hepatocellular carcinoma; mitochondrial pathway apoptosis; p53; tetramethylpyrazine (TMP)