Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan

Tentori,Lucio; Leonetti,Carlo; Muzi,Alessia; Dorio,Annalisa  Susanna; Porru,Manuela; Dolci,Susanna; Campolo,Federica; Vernole,Patrizia; Lacal,Pedro  Miguel; Praz,Françoise; Graziani,Grazia

doi:10.3892/ijo.2013.1932

Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan

Authors:
- Lucio Tentori
- Carlo Leonetti
- Alessia Muzi
- Annalisa Susanna Dorio
- Manuela Porru
- Susanna Dolci
- Federica Campolo
- Patrizia Vernole
- Pedro Miguel Lacal
- Françoise Praz
- Grazia Graziani
View Affiliations

Affiliations: Department of System Medicine, University of Rome ‘Tor Vergata’, I-00133 Rome, Italy, Experimental Preclinical Laboratory, Regina Elena National Cancer Institute, I-00158 Rome, Italy, Department of Biomedicine, University of Rome ‘Tor Vergata’, I-00133 Rome, Italy, Department of Science and Technology of Education, University of Rome ‘Tor Vergata’, I-00133 Rome, Italy, Laboratory of Molecular Oncology, Istituto Dermopatico Dell'Immacolata (IDI), Istituto di Recovero e Cura a Carattere Scientifico (IRCCS)’, I-00167 Rome, Italy, INSERM, UMR_S 938, Saint-Antoine Research Centre, F-75012 Paris, France
Published online on: May 8, 2013 https://doi.org/10.3892/ijo.2013.1932
Pages: 210-218

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Poly(ADP-ribose) polymerase inhibitors (PARPi) are currently evaluated in clinical trials in combination with topoisomerase I (Top1) inhibitors against a variety of cancers, including colon carcinoma. Since the mismatch repair component MLH1 is defective in 10-15% of colorectal cancers we have investigated whether MLH1 affects response to the Top1 inhibitor irinotecan, alone or in combination with PARPi. To this end, the colon cancer cell lines HCT116, carrying MLH1 mutations on chromosome 3 and HCT116 in which the wild-type MLH1 gene was replaced via chromosomal transfer (HCT116+3) or by transfection of the corresponding MLH1 cDNA (HCT116 1-2) were used. HCT116 cells or HCT116+3 cells stably silenced for PARP-1 expression were also analysed. The results of in vitro and in vivo experiments indicated that MLH1, together with low levels of Top1, contributed to colon cancer resistance to irinotecan. In the MLH1-proficient cells SN-38, the active metabolite of irinotecan, induced lower levels of DNA damage than in MLH1-deficient cells, as shown by the weaker induction of γ-H2AX and p53 phosphorylation. The presence of MLH1 contributed to induce of prompt Chk1 phosphorylation, restoring G2/M cell cycle checkpoint and repair of DNA damage. On the contrary, in the absence of MLH1, HCT116 cells showed minor Chk1 phosphorylation and underwent apoptosis. Remarkably, inhibition of PARP function by PARPi or by PARP-1 gene silencing always increased the antitumor activity of irinotecan, even in the presence of low PARP-1 expression.

View Figures

View References

1.	Davies JM and Goldberg RM: Treatment of metastatic colorectal cancer. Semin Oncol. 38:552–560. 2011. View Article : Google Scholar : PubMed/NCBI
2.	Alagoz M, Gilbert DC, El-Khamisy S and Chalmers AJ: DNA repair and resistance to topoisomerase I inhibitors: mechanisms, biomarkers and therapeutic targets. Curr Med Chem. 19:3874–3885. 2012. View Article : Google Scholar : PubMed/NCBI
3.	Miknyoczki SJ, Jones-Bolin S, Pritchard S, Hunter K, Zhao H, Wan W, Ator M, et al: Chemopotentiation of temozolomide, irinotecan and cisplatin activity by CEP-6800, a poly(ADP-ribose) polymerase inhibitor. Mol Cancer Ther. 2:371–382. 2003.PubMed/NCBI
4.	Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, et al: Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst. 96:56–67. 2004. View Article : Google Scholar : PubMed/NCBI
5.	Smith LM, Willmore E, Austin CA and Curtin NJ: The novel poly(ADP-Ribose) polymerase inhibitor, AG14361, sensitizes cells to topoisomerase I poisons by increasing the persistence of DNA strand breaks. Clin Cancer Res. 11:8449–8457. 2005. View Article : Google Scholar : PubMed/NCBI
6.	Tentori L, Leonetti C, Scarsella M, Muzi A, Mazzon E, Vergati M, Forini O, et al: Inhibition of poly(ADP-ribose) polymerase prevents irinotecan-induced intestinal damage and enhances irinotecan/temozolomide efficacy against colon carcinoma. FASEB J. 20:1709–1711. 2006. View Article : Google Scholar
7.	Daniel RA, Rozanska AL, Thomas HD, Mulligan EA, Drew Y, Castelbuono DJ, Hostomsky Z, et al: Inhibition of poly(ADP-ribose) polymerase-1 enhances temozolomide and topotecan activity against childhood neuroblastoma. Clin Cancer Res. 15:1241–1249. 2009. View Article : Google Scholar : PubMed/NCBI
8.	Schreiber V, Dantzer F, Ame JC and de Murcia G: Poly(ADP-ribose): novel functions for an old molecule. Nat Rev Mol Cell Biol. 7:517–528. 2006. View Article : Google Scholar : PubMed/NCBI
9.	Malanga M and Althaus FR: Poly(ADP-ribose) reactivates stalled DNA topoisomerase I, induces DNA strand break resealing. J Biol Chem. 279:5244–5248. 2004. View Article : Google Scholar : PubMed/NCBI
10.	Leonetti C, Biroccio A, Graziani G and Tentori L: Targeted therapy for brain tumours: role of PARP inhibitors. Curr Cancer Drug Targets. 12:218–236. 2012. View Article : Google Scholar : PubMed/NCBI
11.	Martin SA, Lord CJ and Ashworth A: Therapeutic targeting of the DNA mismatch repair pathway. Clin Cancer Res. 16:5107–5113. 2010. View Article : Google Scholar : PubMed/NCBI
12.	D’Atri S, Tentori L, Lacal PM, Graziani G, Pagani E, Benincasa E, Zambruno G, et al: Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol. 54:334–341. 1998.PubMed/NCBI
13.	Tentori L and Graziani G: Recent approaches to improve the antitumor efficacy of temozolomide. Curr Med Chem. 16:245–257. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Fedier A, Schwarz VA, Walt H, Carpini RD, Haller U and Fink D: Resistance to topoisomerase poisons due to loss of DNA mismatch repair. Int J Cancer. 93:571–576. 2001. View Article : Google Scholar : PubMed/NCBI
15.	Jacob S, Aguado M, Fallik D and Praz F: The role of the DNA mismatch repair system in the cytotoxicity of the topoisomerase inhibitors camptothecin and etoposide to human colorectal cancer cells. Cancer Res. 61:6555–6562. 2001.PubMed/NCBI
16.	Magrini R, Bhonde MR, Hanski ML, Notter M, Scherübl H, Boland CR, Zeitz M and Hanski C: Cellular effects of CPT-11 on colon carcinoma cells: dependence on p53 and hMLH1 status. Int J Cancer. 101:23–31. 2002. View Article : Google Scholar : PubMed/NCBI
17.	Fallik D, Borrini F, Boige V, Viguier J, Jacob S, Miquel C, Sabourin JC, et al: Microsatellite instability is a predictive factor of the tumor response to irinotecan in patients with advanced colorectal cancer. Cancer Res. 63:5738–5744. 2003.PubMed/NCBI
18.	Papouli E, Cejka P and Jiricny J: Dependence of the cytotoxicity of DNA-damaging agents on the mismatch repair status of human cells. Cancer Res. 64:3391–3394. 2004. View Article : Google Scholar : PubMed/NCBI
19.	Bhonde MR, Hanski ML, Stehr J, Jebautzke B, Peiró-Jordán R, Fechner H, Yokoyama KK, et al: Mismatch repair system decreases cell survival by stabilizing the tetraploid G1 arrest in response to SN-38. Int J Cancer. 126:2813–2825. 2010.PubMed/NCBI
20.	Martin LP, Hamilton TC and Schilder RJ: Platinum resistance: the role of DNA repair pathways. Clin Cancer Res. 14:1291–1295. 2008. View Article : Google Scholar : PubMed/NCBI
21.	Papadopoulos N, Nicolaides NC, Wei YF, Ruben SM, Carter KC, Rosen CA, Haseltine WA, et al: Mutation of a mutL homolog in hereditary colon cancer. Science. 263:1625–1629. 1994. View Article : Google Scholar : PubMed/NCBI
22.	Koi M, Umar A, Chauhan DP, Cherian SP, Carethers JM, Kunkel TA and Boland CR: Human chromosome 3 corrects mismatch repair deficiency and microsatellite instability and reduces N-methyl-N’-nitro-N-nitrosoguanidine tolerance in colon tumor cells with homozygous hMLH1 mutation. Cancer Res. 54:4308–4312. 1994.PubMed/NCBI
23.	Vernole P, Muzi A, Volpi A, Terrinoni A, Dorio AS, Tentori L, Shah GM and Graziani G: Common fragile sites in colon cancer cell lines: role of mismatch repair, RAD51 and poly(ADP-ribose) polymerase-1. Mutat Res. 712:40–48. 2011. View Article : Google Scholar : PubMed/NCBI
24.	Tentori L, Leonetti C, Scarsella M, D’Amati G, Vergati M, Portarena I, Xu W, et al: Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res. 9:5370–5379. 2003.
25.	Yamane K, Taylor K and Kinsella TJ: Mismatch repair-mediated G2/M arrest by 6-thioguanine involves the ATR-Chk1 pathway. Biochem Biophys Res Commun. 318:297–302. 2004. View Article : Google Scholar : PubMed/NCBI
26.	Yoshioka K, Yoshioka Y and Hsieh P: ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol Cell. 22:501–510. 2006. View Article : Google Scholar : PubMed/NCBI
27.	Adamson AW, Beardsley DI, Kim WJ, Gao Y, Baskaran R and Brown KD: Methylator-induced, mismatch repair-dependent G2 arrest is activated through Chk1 and Chk2. Mol Biol Cell. 16:1513–1526. 2005. View Article : Google Scholar : PubMed/NCBI
28.	Marra G and Jiricny J: DNA mismatch repair and colon cancer. Adv Exp Med Biol. 570:85–123. 2005. View Article : Google Scholar : PubMed/NCBI
29.	Damia G and D’Incalci M: Genetic instability influences drug response in cancer cells. Curr Drug Targets. 11:1317–1324. 2010. View Article : Google Scholar : PubMed/NCBI
30.	Sinicrope FA, Foster NR, Thibodeau SN, Marsoni S, Monges G, Labianca R, Kim GP, et al: DNA mismatch repair status and colon cancer recurrence and survival in clinical trials of 5-fluorouracil-based adjuvant therapy. J Natl Cancer Inst. 103:863–875. 2011. View Article : Google Scholar : PubMed/NCBI
31.	Garner KM and Eastman A: Variations in Mre11/Rad50/Nbs1 status and DNA damage-induced S-phase arrest in the cell lines of the NCI60 panel. BMC Cancer. 206:1–13. 2011.PubMed/NCBI
32.	Takemura H, Rao VA, Sordet O, Furuta T, Miao ZH, Meng L, Zhang H and Pommier Y: Defective Mre11-dependent activation of Chk2 by ataxia telangiectasia mutated in colorectal carcinoma cells in response to replication-dependent DNA double strand breaks. J Biol Chem. 281:30814–30823. 2006. View Article : Google Scholar : PubMed/NCBI
33.	Tentori L, Muzi A, Dorio AS, Scarsella M, Leonetti C, Shah GM, Xu W, et al: Pharmacological inhibition of poly(ADP-ribose) polymerase (PARP) activity in PARP-1 silenced tumour cells increases chemosensitivity to temozolomide and to a N3-adenine selective methylating agent. Curr Cancer Drug Targets. 10:368–383. 2010. View Article : Google Scholar
34.	D’Onofrio G, Tramontano F, Dorio AS, Muzi A, Maselli V, Fulgione D, Graziani G, et al: Poly(ADP-ribose) polymerase signaling of topoisomerase 1-dependent DNA damage in carcinoma cells. Biochem Pharmacol. 81:194–202. 2011.
35.	Patel AG, Flatten KS, Schneider PA, Dai NT, McDonald JS, Poirier GG and Kaufmann SH: Enhanced killing of cancer cells by poly(ADP-ribose) polymerase inhibitors and topoisomerase I inhibitors reflects poisoning of both enzymes. J Biol Chem. 287:4198–4210. 2012. View Article : Google Scholar : PubMed/NCBI
36.	Davidson D, Wang Y, Aloyz R and Panasci L: The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines. Invest New Drugs. 31:461–468. 2013. View Article : Google Scholar : PubMed/NCBI