title: Harmine suppresses homologous recombination repair and inhibits proliferation of hepatoma cells.
abstract: To avoid cell cycle arrest or apoptosis, rapidly proliferating cancer cells have to promote DNA double strand break (DSB) repair to fix replication stress induced DSBs. Therefore, developing drugs blocking homologous recombination (HR) and nonhomologous end joining (NHEJ) - 2 major DSB repair pathways - holds great potential for cancer therapy. Over the last few decades, much attention has been paid to explore drugs targeting DSB repair pathways for cancer therapy. Here, using 2 well-established reporters for analyzing HR and NHEJ efficiency, we found that both HR and NHEJ are elevated in hepatoma cell lines Hep3B and HuH7 compared with normal liver cell lines Chang liver and QSG-7701. Our further study found that Harmine, a natural compound, negatively regulates HR but not NHEJ by interfering Rad51 recruitment, resulting in severe cytotoxicity in hepatoma cells. Furthermore, NHEJ inhibitor Nu7441 markedly sensitizes Hep3B cells to the anti-proliferative effects of Harmine. Taken together, our study suggested that Harmine holds great promise as an oncologic drug and combination of Harmine with a NHEJ inhibitor might be an effective strategy for anti-cancer treatment.
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.|b Department of Plastic Surgery ; Shanghai Changzheng Hospital ; Shanghai , China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhang
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Lu
authors.initials: L
authors.lastname: Chen
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Neng
authors.initials: N
authors.lastname: Gao
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: Men
authors.affiliation: c State Key Laboratory of Natural Medicines; China Pharmaceutical University ; Nanjing , China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Xu
authors.affiliation: a Department of Clinical Laboratory Medicine ; Shanghai Tenth People's Hospital; School of Life Sciences and Technology; Tongji University ; Shanghai , China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D053903:DNA Breaks, Double-Stranded; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints; D006247:Harmine / Q000494:pharmacology*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D051135:Rad51 Recombinase / Q000378:metabolism; D059767:Recombinational DNA Repair; D059807:S Phase Cell Cycle Checkpoints
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D006247:Harmine; C495153:RAD51 protein, human; D051135:Rad51 Recombinase
keywords: DNA double strand break repair; Harmine; Rad51; combination; homologous recombination repair