CURCUMIN MODULATES THE RADIOSENSITIVITY OF COLORECTAL CANCER CELLS BY SUPPRESSING CONSTITUTIVE AND INDUCIBLE NF-κB ACTIVITY

Purpose: Radiation therapy is an integral part of the preoperative treatment of rectal cancers. However, only a minority of patients achieve a complete pathologic response to therapy because of resistance of these tumors to radiation therapy. This resistance may be mediated by constitutively active pro-survival signaling pathways or by inducible/acquired mechanisms in response to radiation therapy. Simultaneous inhibition of these pathways can sensitize these tumors to radiation therapy. Methods and Materials: Human colorectal cancer cells were exposed to clinically relevant doses of gamma rays, and the mechanism of their radioresistance was investigated. We characterized the transcription factor nuclear factor-kappa B (NF-kappa B) activation as a mechanism of inducible radioresistance in colorectal cancer and used curcumin, the active ingredient in the yellow spice turmeric, to overcome this resistance. Results: Curcumin inhibited the proliferation and the post-irradiation clonogenic survival of multiple colorectal cancer cell lines. Radiation stimulated NF-kappa B activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappa B activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappa B alpha, inhibition of inhibitor of kappa B kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappa B-regulated gene products (Bcl-2, BCI-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1). Conclusions: Our results suggest that transient inducible NF-kappa B activation provides a prosurvival response to radiation that may account for development of radioresistance. Curcumin blocks this signaling pathway and potentiates the antitumor effects of radiation therapy. (C) 2009 Elsevier Inc.