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

• Published in: Investigational new drugs Vol. 31; no. 2; pp. 461 - 468
• Main Authors: Davidson, David, Wang, Yunzhe, Aloyz, Raquel, Panasci, Lawrence
• Format: Journal Article
• Language: English
• Published: Boston Springer US 01.04.2013; Springer; Springer Nature B.V
• Subjects: Antineoplastic agents; Antineoplastic Agents, Phytogenic - pharmacology; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis - drug effects; Benzimidazoles - pharmacology; Biological and medical sciences; Blotting, Western; Breast cancer; Camptothecin - analogs & derivatives; Camptothecin - pharmacology; Cancer therapies; Cell cycle; Cell Proliferation - drug effects; Chemotherapy; Clinical trials; Colonic Neoplasms - drug therapy; Colonic Neoplasms - enzymology; Colonic Neoplasms - pathology; Colorectal cancer; Cytotoxicity; DNA damage; DNA repair; Drug Synergism; Drugs; Experiments; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; General aspects; Humans; Inhibitor drugs; Irinotecan; Laboratories; Medical sciences; Medicine; Medicine & Public Health; Metastasis; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Oncology; Pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Poly(ADP-ribose) Polymerase Inhibitors; Proteins; Short Report; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Studies; Tumor Cells, Cultured; Tumors; Canada; Irinotecan; PARP; Colon cancer; VE-821; SN38; PARP inhibitor; Camptothecin derivatives; Antineoplastic agent; Drug combination; Enzyme; DNA topoisomerase; Enzyme inhibitor; Malignant tumor; In vitro; Colonic disease; Isomerases; Treatment; Established cell line; Digestive diseases; Intestinal disease; Topoisomerase I inhibitor; Tumor cell; Cancer
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-012-9886-7

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.