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The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines

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Summary

Poly [ADP-ribose] polymerase-1 (PARP-1) localizes rapidly to sites of DNA damage and has been associated with various repair mechanisms including base excision repair (BER) and homologous recombination/non-homologous end joining (HRR/NHEJ). PARP-1 acts by adding poly-ADP ribose side chains to target proteins (PARylation) altering molecular interactions and functions. Recently small molecule inhibitors of PARP-1 have been shown to have significant clinical potential and third generation PARP inhibitors are currently being investigated in clinical trials. These drugs alone or in combination with radio/chemotherapy have resulted in meaningful patient responses and an increase in survival in metastatic breast cancer cases bearing BRCA-deficient or triple negative tumors and BRCA-deficient ovarian cancer patients. ABT-888, a potent PARP-1 inhibitor, sensitizes many cancer cells in-vitro and in-vivo to temozolomide. As such, we hypothesized that colon cancers would be sensitized to the DNA damaging chemotherapeutic agents, oxaliplatin and irinotecan, by ABT-888. Using colon cancer cell lines significant synergy was observed between ABT-888 and irinotecan at concentrations of ABT-888 as low as 0.125 μM. The level of synergy observed correlated with the degree of PARP1 inhibition as measured biochemically in cell lysates. ABT-888 at concentrations of 0.5–4 μM resulted in synergy with oxaliplatin. Furthermore, 24 h post treatment combinations of ABT-888/irinotecan generally resulted in increased G2/M cell cycle arrest and increased levels of DNA damage, followed by increased levels of apoptosis 48 h post treatment. In conclusion this study suggests that ABT-888 may be a clinically effective adjuvant to current colon cancer therapies that include the use of irinotecan and/or oxaliplatin.

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Acknowledgements

We gratefully acknowledge Abbott laboratories for providing the PARP inhibitor ABT-888 used in this study.

Grant support

This work was supported by research grants to Lawrence Panasci and Raquel Aloyz from the Canadian Institute of Health Research (CIHR) and CIHR and the Leukemia, Lymphoma Society (USA), respectively. David Davidson received salary support from the Quebec-Clinical Research Organization in Cancer (Q-CROC).

Conflict of interest

The authors declare they have no conflict of interest.

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Authors and Affiliations

  1. Montreal Centre for Experimental Therapeutics in Cancer—Segal Cancer Center—Lady Davis Institute—Jewish General Hospital, McGill University, 3755, Côte Sainte Catherine Road, Montréal, Québec, H3T 1E2, Canada

    David Davidson, Yunzhe Wang, Raquel Aloyz & Lawrence Panasci

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  1. David Davidson
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  2. Yunzhe Wang
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  3. Raquel Aloyz
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  4. Lawrence Panasci
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Correspondence to Raquel Aloyz or Lawrence Panasci.

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Davidson, D., Wang, Y., Aloyz, R. et al. The PARP inhibitor ABT-888 synergizes irinotecan treatment of colon cancer cell lines. Invest New Drugs 31, 461–468 (2013). https://doi.org/10.1007/s10637-012-9886-7

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  • DOI: https://doi.org/10.1007/s10637-012-9886-7

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