DNA Repair Pathways and Cisplatin Resistance: an Intimate Relationship

Overview

Journal Clinics (Sao Paulo)

Publisher Elsevier

Specialty General Medicine

Date 2018 Sep 13

PMID 30208165

Citations 192

Authors

Clarissa Ribeiro Reily Rocha

Matheus Molina Silva

Annabel Quinet

Januario Bispo Cabral-Neto

Carlos Frederico Martins Menck

Affiliations

Soon will be listed here.

Abstract

The main goal of chemotherapeutic drugs is to induce massive cell death in tumors. Cisplatin is an antitumor drug widely used to treat several types of cancer. Despite its remarkable efficiency, most tumors show intrinsic or acquired drug resistance. The primary biological target of cisplatin is genomic DNA, and it causes a plethora of DNA lesions that block transcription and replication. These cisplatin-induced DNA lesions strongly induce cell death if they are not properly repaired or processed. To counteract cisplatin-induced DNA damage, cells use an intricate network of mechanisms, including DNA damage repair and translesion synthesis. In this review, we describe how cisplatin-induced DNA lesions are repaired or tolerated by cells and focus on the pivotal role of DNA repair and tolerance mechanisms in tumor resistance to cisplatin. In fact, several recent clinical findings have correlated the tumor cell status of DNA repair/translesion synthesis with patient response to cisplatin treatment. Furthermore, these mechanisms provide interesting targets for pharmacological modulation that can increase the efficiency of cisplatin chemotherapy.

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References

Esteller M . Epigenetic lesions causing genetic lesions in human cancer: promoter hypermethylation of DNA repair genes. Eur J Cancer. 2000; 36(18):2294-300. DOI: 10.1016/s0959-8049(00)00303-8. View

Menck C, Munford V . DNA repair diseases: What do they tell us about cancer and aging?. Genet Mol Biol. 2014; 37(1 Suppl):220-33. PMC: 3983582. DOI: 10.1590/s1415-47572014000200008. View

Neher T, Bodenmiller D, Fitch R, Jalal S, Turchi J . Novel irreversible small molecule inhibitors of replication protein A display single-agent activity and synergize with cisplatin. Mol Cancer Ther. 2011; 10(10):1796-806. PMC: 3191262. DOI: 10.1158/1535-7163.MCT-11-0303. View

Fram R, Cusick P, Wilson J, Marinus M . Mismatch repair of cis-diamminedichloroplatinum(II)-induced DNA damage. Mol Pharmacol. 1985; 28(1):51-5. View

Sale J . Competition, collaboration and coordination--determining how cells bypass DNA damage. J Cell Sci. 2012; 125(Pt 7):1633-43. DOI: 10.1242/jcs.094748. View

Metzger R, Leichman C, Danenberg K, Danenberg P, Lenz H, Hayashi K . ERCC1 mRNA levels complement thymidylate synthase mRNA levels in predicting response and survival for gastric cancer patients receiving combination cisplatin and fluorouracil chemotherapy. J Clin Oncol. 1998; 16(1):309-16. DOI: 10.1200/JCO.1998.16.1.309. View

Scartozzi M, De Nictolis M, Galizia E, Carassai P, Bianchi F, Berardi R . Loss of hMLH1 expression correlates with improved survival in stage III-IV ovarian cancer patients. Eur J Cancer. 2003; 39(8):1144-9. DOI: 10.1016/s0959-8049(03)00197-7. View

Alagpulinsa D, Ayyadevara S, Shmookler Reis R . A Small-Molecule Inhibitor of RAD51 Reduces Homologous Recombination and Sensitizes Multiple Myeloma Cells to Doxorubicin. Front Oncol. 2014; 4:289. PMC: 4214226. DOI: 10.3389/fonc.2014.00289. View

Martin L, Hamilton T, Schilder R . Platinum resistance: the role of DNA repair pathways. Clin Cancer Res. 2008; 14(5):1291-5. DOI: 10.1158/1078-0432.CCR-07-2238. View

10.

Lin X, Trang J, Okuda T, Howell S . DNA polymerase zeta accounts for the reduced cytotoxicity and enhanced mutagenicity of cisplatin in human colon carcinoma cells that have lost DNA mismatch repair. Clin Cancer Res. 2006; 12(2):563-8. DOI: 10.1158/1078-0432.CCR-05-1380. View

11.

Cummings M, Higginbottom K, McGurk C, Wong O, Koberle B, Oliver R . XPA versus ERCC1 as chemosensitising agents to cisplatin and mitomycin C in prostate cancer cells: role of ERCC1 in homologous recombination repair. Biochem Pharmacol. 2006; 72(2):166-75. DOI: 10.1016/j.bcp.2006.04.025. View

12.

Hicks J, Chute C, Paulsen M, Ragland R, Howlett N, Gueranger Q . Differential roles for DNA polymerases eta, zeta, and REV1 in lesion bypass of intrastrand versus interstrand DNA cross-links. Mol Cell Biol. 2009; 30(5):1217-30. PMC: 2820889. DOI: 10.1128/MCB.00993-09. View

13.

Bowden N . Nucleotide excision repair: why is it not used to predict response to platinum-based chemotherapy?. Cancer Lett. 2014; 346(2):163-71. DOI: 10.1016/j.canlet.2014.01.005. View

14.

Masutani C, KUSUMOTO R, Iwai S, Hanaoka F . Mechanisms of accurate translesion synthesis by human DNA polymerase eta. EMBO J. 2000; 19(12):3100-9. PMC: 203367. DOI: 10.1093/emboj/19.12.3100. View

15.

Vaisman A, Masutani C, Hanaoka F, Chaney S . Efficient translesion replication past oxaliplatin and cisplatin GpG adducts by human DNA polymerase eta. Biochemistry. 2000; 39(16):4575-80. DOI: 10.1021/bi000130k. View

16.

Park J, Long D, Lee K, Abbas T, Shibata E, Negishi M . The MCM8-MCM9 complex promotes RAD51 recruitment at DNA damage sites to facilitate homologous recombination. Mol Cell Biol. 2013; 33(8):1632-44. PMC: 3624244. DOI: 10.1128/MCB.01503-12. View

17.

Xie K, Doles J, Hemann M, Walker G . Error-prone translesion synthesis mediates acquired chemoresistance. Proc Natl Acad Sci U S A. 2010; 107(48):20792-7. PMC: 2996453. DOI: 10.1073/pnas.1011412107. View

18.

Hsu H, Wen C, Tang Y, Lin R, Li W, Hsu W . Promoter hypermethylation is the predominant mechanism in hMLH1 and hMSH2 deregulation and is a poor prognostic factor in nonsmoking lung cancer. Clin Cancer Res. 2005; 11(15):5410-6. DOI: 10.1158/1078-0432.CCR-05-0601. View

19.

Plumb J, Strathdee G, Sludden J, Kaye S, Brown R . Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. Cancer Res. 2000; 60(21):6039-44. View

20.

Smith J, Tho L, Xu N, Gillespie D . The ATM-Chk2 and ATR-Chk1 pathways in DNA damage signaling and cancer. Adv Cancer Res. 2010; 108:73-112. DOI: 10.1016/B978-0-12-380888-2.00003-0. View