title: Hyperthermia enhances 17-DMAG efficacy in hepatocellular carcinoma cells with aggravated DNA damage and impaired G2/M transition.
abstract: Due to the lack of effective treatment, hepatocellular carcinoma (HCC) is one of the malignancies with low survival rates worldwide. Combination of hyperthermia and chemotherapy has shown promising results in several abdominal tumours, but high expression of HSP90 in tumours attenuated the efficacy of hyperthermia. Thus a combination of hyperthermia and inhibition of HSP90 might be a feasible therapeutic strategy for HCC. One hepatic cell line (L02) and two HCC cell lines (Huh7 and HepG2) were heated at 42 °C for 0, 0.5 or 4 h with or without 100 nM 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG). HCC cells of the combination group exhibited more G2/M arrest and higher apoptotic rates which might result from suffering from more reactive oxygen species and serious DNA damage. Heat shock/17-DMAG co-treatment of HCC cells also destabilized CDK1, Cyclin B1 and CDC25C with a concomitant decreased proportion of cells in the M phase. Furthermore, co-treatment impaired the interaction of HSP90α with CDC37 and with CDK1, accompanied with decreased soluble CDK1. Combination of 17-DMAG with a 1.5-h whole body hyperthermia treatment attenuated tumour growth in xenograft mice models. These results suggest hyperthermia sensitize HCC to 17-DMAG, and combination of hyperthermia with 17-DMAG might be a potential therapeutic strategy for HCC.
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Zhizhou
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xueqiong
authors.initials: X
authors.lastname: Zhou
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Yangfan
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Ke
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Zou
authors.affiliation: Department of Occupational Health and Medicine, School of Public Health, Southern Medical University, 1838 Guangzhou Road North, Guangzhou, 510515, China.
authors.forename: Xuemei
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018833:Chaperonins / Q000378:metabolism; D056744:Cyclin B1 / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008807:Mice, Inbred BALB C; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016227:Benzoquinones; C534699:CCNB1 protein, human; C498362:CDC37 protein, human; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D017382:Reactive Oxygen Species; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018833:Chaperonins