4.6 Article

Olaparib-mediated enhancement of 5-fluorouracil cytotoxicity in mismatch repair deficient colorectal cancer cells

期刊

BMC CANCER
卷 21, 期 1, 页码 -

出版社

BMC
DOI: 10.1186/s12885-021-08188-7

关键词

Colorectal cancer; Mismatch repair; 5-fluorouracil; PARP; Olaparib

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资金

  1. FAPERGS (Fundacao de Amparo a Pesquisa do Estado do Rio Grande do Sul, Porto Alegre, Brazil) [16/2551-0000 473-0, 17/2551-0001 459-6]
  2. CNPq (Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brasilia, Brazil) [423039/2016-4]
  3. CAPES (Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brasilia, Brazil)
  4. CAPES

向作者/读者索取更多资源

Our study demonstrated that Olaparib enhances the cytotoxicity of 5-FU in MMR-deficient CRC cells, while it reduces clonogenic survival and induces DNA damage in MMR-proficient CRC cells. Combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.
BackgroundThe advances in colorectal cancer (CRC) treatment include the identification of deficiencies in Mismatch Repair (MMR) pathway to predict the benefit of adjuvant 5-fluorouracil (5-FU) and oxaliplatin for stage II CRC and immunotherapy. Defective MMR contributes to chemoresistance in CRC. A growing body of evidence supports the role of Poly-(ADP-ribose) polymerase (PARP) inhibitors, such as Olaparib, in the treatment of different subsets of cancer beyond the tumors with homologous recombination deficiencies. In this work we evaluated the effect of Olaparib on 5-FU cytotoxicity in MMR-deficient and proficient CRC cells and the mechanisms involved.MethodsHuman colon cancer cell lines, proficient (HT29) and deficient (HCT116) in MMR, were treated with 5-FU and Olaparib. Cytotoxicity was assessed by MTT and clonogenic assays, apoptosis induction and cell cycle progression by flow cytometry, DNA damage by comet assay. Adhesion and transwell migration assays were also performed.ResultsOur results showed enhancement of the 5-FU citotoxicity by Olaparib in MMR-deficient HCT116 colon cancer cells. Moreover, the combined treatment with Olaparib and 5-FU induced G2/M arrest, apoptosis and polyploidy in these cells. In MMR proficient HT29 cells, the Olaparib alone reduced clonogenic survival, induced DNA damage accumulation and decreased the adhesion and migration capacities.ConclusionOur results suggest benefits of Olaparib inclusion in CRC treatment, as combination with 5-FU for MMR deficient CRC and as monotherapy for MMR proficient CRC. Thus, combined therapy with Olaparib could be a strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.

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