title: Involvement of homologous recombination in the synergism between cisplatin and poly (ADP-ribose) polymerase inhibition.
abstract: Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options.
authors.affiliation: Department of Cellular Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan; Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Sakogawa
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Aoki
authors.forename: Keizo
authors.initials: K
authors.lastname: Misumi
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Hamai
authors.forename: Manabu
authors.initials: M
authors.lastname: Emi
authors.forename: Jun
authors.initials: J
authors.lastname: Hihara
authors.forename: Lin
authors.initials: L
authors.lastname: Shi
authors.forename: Kazuteru
authors.initials: K
authors.lastname: Kono
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Horikoshi
authors.forename: Jiying
authors.initials: J
authors.lastname: Sun
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Ikura
authors.forename: Morihito
authors.initials: M
authors.lastname: Okada
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tashiro
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D053903:DNA Breaks, Double-Stranded; D004260:DNA Repair / Q000235:genetics*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004938:Esophageal Neoplasms / Q000201:enzymology*; D000077277:Esophageal Squamous Cell Carcinoma; D005472:Fluorouracil / Q000494:pharmacology; D006657:Histones / Q000378:metabolism; D059765:Homologous Recombination / Q000235:genetics*; D006801:Humans; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000187:drug effects; D034622:RNA Interference; D034741:RNA, Small Interfering; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism
chemical_list: D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; C468783:H2AX protein, human; D006657:Histones; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D034741:RNA, Small Interfering; C025160:3-aminobenzamide; D011065:Poly(ADP-ribose) Polymerases; C495153:RAD51 protein, human; D051135:Rad51 Recombinase; D002945:Cisplatin; D005472:Fluorouracil
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