title: The use of Olaparib (AZD2281) potentiates SN-38 cytotoxicity in colon cancer cells by indirect inhibition of Rad51-mediated repair of DNA double-strand breaks.
abstract: Potent application of topoisomerase I inhibitor plus PARP inhibitor has been suggested to be an effective strategy for cancer therapy. Reportedly, mismatch repair (MMR)-deficient colon cancer cells are sensitive to topoisomerase I inhibitor, presumably due to microsatellite instability (MSI) of the MRE11 locus. We examined the synergy of SN-38, an active metabolite of irinotecan, in combination with the PARP inhibitor olaparib in colon cancer cells showing different MMR status, such as MSI or microsatellite stable (MSS) phenotype. Treatment with SN-38 and olaparib in combination almost halved the IC50 of SN-38 for a broad spectrum of colon cancer cells independent of the MMR status. Furthermore, olaparib potentiated S-phase-specific double-strand DNA breaks (DSB) induced by SN-38, which is followed by Rad51 recruitment. siRNA-mediated knockdown of Rad51, but not Mre11 or Rad50, increased the sensitivity to olaparib and/or SN-38 treatment in colon cancer cells. In vivo study using mouse xenograft demonstrated that olaparib was effective to potentiate the antitumor effect of irinotecan. In conclusion, olaparib shows a synergistic effect in colon cancer cells in combination with SN-38 or irinotecan, potentiated by the Rad51-mediated HR pathway, irrespective of the Mre11-mediated failure of the MRN complex. These results may contribute to future clinical trials using PARP inhibitor plus topoisomerase I inhibitor in combination. Furthermore, the synergistic effect comprising topoisomerase I-mediated DNA breakage-reunion reaction, PARP and Rad51-mediated HR pathway suggests the triple synthetic lethal pathways contribute to this event and are applicable as a potential target for future chemotherapy.
authors.affiliation: Authors' Affiliations: Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Department of Surgery, Tochigi Cancer Center, Utsunomiya; and Department of Gastrointestinal Surgery and Division of Clinical Oncology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Tahara
authors.forename: Takeshi
authors.initials: T
authors.lastname: Inoue
authors.forename: Futoshi
authors.initials: F
authors.lastname: Sato
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Miyakura
authors.forename: Hisanaga
authors.initials: H
authors.lastname: Horie
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yasuda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Fujii
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Kotake
authors.forename: Kokichi
authors.initials: K
authors.lastname: Sugano
mesh_terms: D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects*; D053843:DNA Mismatch Repair / Q000187:drug effects; D004260:DNA Repair / Q000187:drug effects*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D051135:Rad51 Recombinase / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D010793:Phthalazines; D010879:Piperazines; D000077146:Irinotecan; D011065:Poly(ADP-ribose) Polymerases; D051135:Rad51 Recombinase; C531550:olaparib; D002166:Camptothecin