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Invest New Drugs. 2013 Apr;31(2):461-8. doi: 10.1007/s10637-012-9886-7. Epub 2012 Oct 9.

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

Author information

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.

Abstract

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.

PMID:
23054213
PMCID:
PMC3857790
DOI:
10.1007/s10637-012-9886-7
[Indexed for MEDLINE]
Free PMC Article

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