Involvement of homologous recombination in the synergism between cisplatin and poly (ADP-ribose) polymerase inhibition

シスプラチンとポリ(ADP-リボース)ポリメラーゼ阻害の併用効果には相同組換え修復機構が関与する

迫川 賢士

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.

医学 [ 490 ]

英語

Copyright(c) by Author

[作成日] 2014-11-21

Kenji Sakogawa, Yoshiro Aoki, Keizo Misumi, Yoichi Hamai, Manabu Emi, Jun Hihara, Lin Shi, Kazuteru Kono, Yasunori Horikoshi, Jiying Sun, Tsuyoshi Ikura, Morihito Okada and Satoshi Tashiro; Involvement of homologous recombination in the synergism between cisplatin and poly (ADP-ribose) polymerase inhibition; Cancer Science, Volume 104, Issue 12, pages 1593-1599, December 2013 (doi: 10.1111/cas.12281) ～を参照している

[DOI] http://dx.doi.org/10.1111/cas.12281 ～を参照している

広島大学