INO-1001, a novel inhibitor of poly(ADP-ribose) polymerase, enhances tumor response to doxorubicin
- 258 Downloads
Poly(ADP-ribose) synthetase inhibitor, INO-1001, is known to sensitize cells to radiation in vitro by inhibiting the repair of DNA damage. Recent evidence has suggested that PARP inhibition may also be a way of selectively targeting p53 deficient cancer cells. The present study tested INO-1001 for its in vivo effect on the chemoresponse of two p53 deficient tumors, human breast cancer MDA-MB-231 and murine mammary carcinoma MCa-K. Doxorubicin was used as the DNA damaging agent and tumor growth delay assay was used as the endpoint. Results showed that INO-1001 was highly effective in enhancing the anti-tumor effects of Doxorubicin for both MDA-MB-231 (EF = 1.88) and MCa-K (EF = 1.64). We conclude that PARP inhibitor INO-1001 has high potential for enhancing the anti-tumor effects of chemotherapy agents such as Doxorubicin against p53 deficient breast cancer.
KeywordsPoly(ADP-ribose) INO-1001 Doxorubicin p53-Deficient cancer cells Doxorubicin-induced apoptosis
Sponsored by a Laboratory Study Agreement with Inotek Pharmaceuticals Corp and NIH Grants CA06294 and CA16672.
- 1.Althaus FR (1985) ADP-Ribosylation of Proteins. Springer, BerlinGoogle Scholar
- 4.Lunee J, George M, Hedges M, Cramp W, Wish W, Hunt B (1984) Post-irradiation sensitization with the ADP-ribosyltransferase inhibitor 3-acetamidobenzamide. Br J Cancer 49:19–25Google Scholar
- 5.Brown D, Evans J, Brown J (1984) The influence of inhibitors of poly(ADP)polymerase on X-ray induced potentially lethal damage repair. Br J Cancer 49:27–34Google Scholar
- 14.Delaney CA, Wang LZ, Kyle S, White AW, Calvert AH, Curtin N, Durkacz B, Hostomsky Z, Newell D (2000) Potentiation of temozolomide and topotecan growth inhibition and cytotoxicity by novel poly(adenosine diphosphoribose) polymerase inhibitors in a panel of human tumor cell lines. Clin Cancer Res 6(7):2860–2867PubMedGoogle Scholar
- 16.Calabrese CR, Almassy R, Barton S, Batey MA, Calvert AH, Canan-Koch S, Durkacz BW, Hostomsky Z, Kumpf RA, Kyle S, Li J, Maegley K, Newell DR, Notarianni E, Stratford IJ, Skalitzky D, Thomas HD, Wang LZ, Webber SE, Williams KJ, Curtin NJ (2004) Anticancer chemosensitization and radiosensitization by the novel poly(ADP-ribose) polymerase-1 inhibitor AG14361. J Natl Cancer Inst 96(1):56–67PubMedCrossRefGoogle Scholar
- 20.Xiao CY, Chen M, Zsengeller Z, Li H, Kiss L, Kollai M, Szabo C (2005) Poly (ADP-Ribose) polymerase promotes cardiac remodeling, contractile failure, and translocation of apoptosis-inducing factor in a murine experimental model of aortic banding and heart failure. J Pharmacol Exp Ther 312(3):891–898PubMedCrossRefGoogle Scholar