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

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.

• Authors: David Davidson, Yunzhe Wang, Raquel Aloyz, Lawrence Panasci
• Journal: Investigational new drugs (Invest New Drugs) Vol. 31 Issue 2 Pg. 461-8 (Apr 2013) ISSN: 1573-0646 [Electronic] United States
• PMID: 23054213 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• Benzimidazoles
• Poly(ADP-ribose) Polymerase Inhibitors
• veliparib
• Irinotecan
• Camptothecin

Topics

• Antineoplastic Agents, Phytogenic (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Benzimidazoles (pharmacology)
• Blotting, Western
• Camptothecin (analogs & derivatives, pharmacology)
• Cell Proliferation (drug effects)
• Colonic Neoplasms (drug therapy, enzymology, pathology)
• Drug Synergism
• Flow Cytometry
• Humans
• Irinotecan
• Poly(ADP-ribose) Polymerase Inhibitors
• Tumor Cells, Cultured