title: Oxaliplatin regulates DNA repair responding to ionizing radiation and enhances radiosensitivity of human cervical cancer cells.
abstract: Concurrent chemoradiotherapy is a standard treatment of locally advanced cervical carcinoma. The most widely used drug for chemoirradiation is cisplatin. However, its toxicity and drug resistance remain major concerns in clinical practice. This study was designed to evaluate the effect of oxaliplatin, another platinum compound, on enhancing radiosensitivity in cervical cancer cell lines. Human HeLa and SiHa cells were used. Cell survival after irradiation with or without oxaliplatin pretreatment was assessed by performing colony-formation assays. Sensitizer enhancement ratios were calculated using a linear quadratic model. Cell morphology was observed after staining with Wright dye. To evaluate the machinery to repair DNA damage, cellular protein was subjected to Western blotting to assess the expression of damage-related molecules. Nontoxic doses of oxaliplatin were 5 and 10 micromol/L for HeLa and SiHa cells, respectively. Pretreatment with oxaliplatin markedly decreased, with a greater extent than cisplatin, the survival of irradiated HeLa cells. Maximal sensitizer enhancement ratios of oxaliplatin at 37% survival were 3.4 for HeLa cells and 4.8 for SiHa cells. Oxaliplatin pretreatment enhanced the cell cycle arrest in the G2/M phase and the radiation-induced mitotic catastrophe. Oxaliplatin modulated radiation-induced DNA double-strand breaks, as indicated by delayed abrogation of gamma-H2AX, attenuation of radiation-induced phosphorylation of ataxia telangiectasia-mutated kinase and checkpoint kinase 2. In conclusion, oxaliplatin sensitized human HeLa and SiHa cells to ionizing radiation. This effect may involve modulation of ataxia telangiectasia-mutated kinase and checkpoint kinase 2 activation during DNA damage repair.
authors.affiliation: Department of Gynecology and Obstetrics, Mackay Memorial Hospital, Taipei, Taiwan.
authors.forename: Yuh-Cheng
authors.initials: YC
authors.lastname: Yang
authors.forename: K S Clifford
authors.initials: KS
authors.lastname: Chao
authors.forename: Chin-Ping
authors.initials: CP
authors.lastname: Lin
authors.forename: Yu-Yawn
authors.initials: YY
authors.lastname: Chen
authors.forename: Kung-Liahng
authors.initials: KL
authors.lastname: Wang
authors.forename: Yu-Jen
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D003131:Combined Modality Therapy; D004260:DNA Repair / Q000187:drug effects* / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006367:HeLa Cells; D006657:Histones / Q000096:biosynthesis; D006801:Humans; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D000077150:Oxaliplatin; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011836:Radiation Tolerance / Q000187:drug effects; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009944:Organoplatinum Compounds; D025521:Tumor Suppressor Proteins; D000077150:Oxaliplatin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases