title: INHIBITORY EFFECT OF TETRAMETHYLPYRAZINE ON HEPATOCELLULAR CARCINOMA: POSSIBLE ROLE OF APOPTOSIS AND CELL CYCLE ARREST.
abstract: Hepatocellular carcinoma (HCC) is the fifth most common cancer. An important approach to control HCC is chemoprevention. This study aims at investigating the antitumor effect of Tetramethylpyrazine (TMP). Rats were injected with N-Nitrosodiethylamine (DEN) to establish HCC. Tumor development was observed. Liver function was evaluated. Apoptosis and cell cycle arrest-related makers and signaling cascades were determined by Western blot, RT-PCR and flow cytometric analysis. The administration of TMP could significantly inhibit tumor development in DEN-induced HCC rats, shown by reduced incidence of tumor, decreased number of tumor nodules and reduced maximal size of tumor. DEN-induced increase of aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase and alkaline phosphatase activities were significantly inhibited by TMP. TMP exhibited inhibitory effect on HCC through induction of apoptosis and cell cycle arrest in rats. TMP induced apoptosis through increasing Bax, decreasing Bcl-2, increasing the release of cytochrome c, and activating caspase, which consisted of the mitochondrial apoptotic pathway. TMP induced G2/M cell cycle arrest through down-regulation of cyclin B1/cdc2. In addition, inhibition of Akt and ERK signaling and the antioxidant activities of TMP may also contribute to its antitumor effect. These data provide new insight into the mechanisms underlying the antitumor effect of TMP.
authors.affiliation: Department of Dermatology, Xijing Hospital, Fourth Military Medical University, Xian, China.
authors.forename: J
authors.initials: J
authors.lastname: Cao
authors.affiliation: Department of Pharmacy, 401 Military Hospital, Qingdao, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Miao
authors.affiliation: Department of Hand Surgery, 401 Military Hospital, Qingdao, China.
authors.forename: J
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: S
authors.initials: S
authors.lastname: Miao
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: L
authors.initials: L
authors.lastname: Bi
authors.affiliation: Department of Pharmacy, Tangdu Hospital, Fourth Military Medical University, Xian, China.
authors.forename: S
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Yang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: M
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Xie
authors.affiliation: Institute of Materia Medica, Fourth Military Medical University, Xian, China.
authors.forename: S
authors.initials: S
authors.lastname: Wang
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D001219:Aspartate Aminotransferases / Q000097:blood; D002453:Cell Cycle / Q000187:drug effects; D004052:Diethylnitrosamine; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D008114:Liver Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008930:Mitochondria, Liver / Q000187:drug effects; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D010084:Oxidation-Reduction; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins; D011719:Pyrazines; D004052:Diethylnitrosamine; D007770:L-Lactate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; C017953:tetramethylpyrazine