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.
Highlights
Colorectal cancer is the third most common cancer in men and the second in women worldwide, while almost 60% of the cases occur in developed countries
The IC50s of SN-38 were lower in MMR-deficient cells harboring homozygous mutations in MRE11 and genetic or epigenetic alterations of MLH1 as compared with the MMR-proficient cells, suggesting that Mre11 deficiency brought about the sensitization of the MMR-deficient cells to the topoisomerase I inhibitor [19, 34, 39]
We counted the number of the 53BP1 foci formation in 2 cell lines, HCT116 and HT29 exposed to SN-38 or SN-38 plus olaparib for 12 hours: the former as a SN-38–sensitive cell line and the latter as a SN-38–resistant one
Summary
Colorectal cancer is the third most common cancer in men and the second in women worldwide, while almost 60% of the cases occur in developed countries. Colorectal cancer is estimated to be the cause of about 8% of all cancer-related deaths, making it the fourth most common cause [1]. 5-fluorouracil (5-FU) and its analogs were employed as the first-line or adjuvant chemotherapy for colon cancer, while cases relapsing after 5-FU–based adjuvant chemotherapy were mostly resistant to 5-FU–based systemic chemotherapy. Irinotecan (CPT-11) was introduced as a drug effective for 5-FU–resistant colorectal cancer, the molecular target of which is type I topoisomerase. Either FOLFOX (5-FU þ leucovorin þ oxaliplatin) or FOLFIRI (5-FU þ leucovorin þ irinotecan) is recommended as the first-line regimen for stage IV colorectal cancer
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