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Article

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 / Copyright

    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
  • Pages: 210-218
    |
    Published online on: May 8, 2013
       https://doi.org/10.3892/ijo.2013.1932
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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.
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Copy and paste a formatted citation
Spandidos Publications style
Tentori L, Leonetti C, Muzi A, Dorio AS, Porru M, Dolci S, Campolo F, Vernole P, Lacal PM, Praz F, Praz F, et al: Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan. Int J Oncol 43: 210-218, 2013.
APA
Tentori, L., Leonetti, C., Muzi, A., Dorio, A.S., Porru, M., Dolci, S. ... Graziani, G. (2013). Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan. International Journal of Oncology, 43, 210-218. https://doi.org/10.3892/ijo.2013.1932
MLA
Tentori, L., Leonetti, C., Muzi, A., Dorio, A. S., Porru, M., Dolci, S., Campolo, F., Vernole, P., Lacal, P. M., Praz, F., Graziani, G."Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan". International Journal of Oncology 43.1 (2013): 210-218.
Chicago
Tentori, L., Leonetti, C., Muzi, A., Dorio, A. S., Porru, M., Dolci, S., Campolo, F., Vernole, P., Lacal, P. M., Praz, F., Graziani, G."Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan". International Journal of Oncology 43, no. 1 (2013): 210-218. https://doi.org/10.3892/ijo.2013.1932
Copy and paste a formatted citation
x
Spandidos Publications style
Tentori L, Leonetti C, Muzi A, Dorio AS, Porru M, Dolci S, Campolo F, Vernole P, Lacal PM, Praz F, Praz F, et al: Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan. Int J Oncol 43: 210-218, 2013.
APA
Tentori, L., Leonetti, C., Muzi, A., Dorio, A.S., Porru, M., Dolci, S. ... Graziani, G. (2013). Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan. International Journal of Oncology, 43, 210-218. https://doi.org/10.3892/ijo.2013.1932
MLA
Tentori, L., Leonetti, C., Muzi, A., Dorio, A. S., Porru, M., Dolci, S., Campolo, F., Vernole, P., Lacal, P. M., Praz, F., Graziani, G."Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan". International Journal of Oncology 43.1 (2013): 210-218.
Chicago
Tentori, L., Leonetti, C., Muzi, A., Dorio, A. S., Porru, M., Dolci, S., Campolo, F., Vernole, P., Lacal, P. M., Praz, F., Graziani, G."Influence of MLH1 on colon cancer sensitivity to poly(ADP-ribose) polymerase inhibitor combined with irinotecan". International Journal of Oncology 43, no. 1 (2013): 210-218. https://doi.org/10.3892/ijo.2013.1932
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