title: Hsp90 inhibitor geldanamycin enhances the antitumor efficacy of enediyne lidamycin in association with reduced DNA damage repair.
abstract: Inhibition of heat shock protein 90 (Hsp90) leads to inappropriate processing of proteins involved in DNA damage repair pathways after DNA damage and may enhance tumor cell radio- and chemo-therapy sensitivity. To investigate the potentiation of antitumor efficacy of lidamycin (LDM), an enediyne agent by the Hsp90 inhibitor geldanamycin (GDM), and possible mechanisms, we have determined effects on ovarian cancer SKOV- 3, hepatoma Bel-7402 and HepG2 cells by MTT assay, apoptosis assay, and cell cycle analysis. DNA damage was investigated with H2AX C-terminal phosphorylation (γH2AX) assays. We found that GDM synergistically sensitized SKOV-3 and Bel-7402 cells to the enediyne LDM, and this was accompanied by increased apoptosis. GDM pretreatment resulted in a greater LDM-induced DNA damage and reduced DNA repair as compared with LDM alone. However, in HepG2 cells GDM did not show significant sensitizing effects both in MTT assay and in DNA damage repair. Abrogation of LDM-induced G2/M arrest by GDM was found in SKOV-3 but not in HepG2 cells. Furthermore, the expression of ATM, related to DNA damage repair responses, was also decreased by GDM in SKOV-3 and Bel-7402 cells but not in HepG2 cells. These results demonstrate that Hsp90 inhibitors may potentiate the antitumor efficacy of LDM, possibly by reducing the repair of LDM-induced DNA damage.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China E-mail : zhenys@public.bta.net.cn.
authors.forename: Fei-Fei
authors.initials: FF
authors.lastname: Han
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Bo-Yang
authors.initials: BY
authors.lastname: Shang
authors.forename: Rong-Guang
authors.initials: RG
authors.lastname: Shao
authors.forename: Yong-Su
authors.initials: YS
authors.lastname: Zhen
mesh_terms: D000617:Aminoglycosides / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D016227:Benzoquinones / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D053281:Enediynes / Q000494:pharmacology*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D056945:Hep G2 Cells; D006657:Histones / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D010766:Phosphorylation
chemical_list: D000617:Aminoglycosides; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D053281:Enediynes; C468783:H2AX protein, human; D018841:HSP90 Heat-Shock Proteins; D006657:Histones; D047029:Lactams, Macrocyclic; C058024:C 1027; C001277:geldanamycin