1. Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity.
- Author
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Sandur SK, Deorukhkar A, Pandey MK, Pabón AM, Shentu S, Guha S, Aggarwal BB, and Krishnan S
- Subjects
- Apoptosis, Cell Line, Tumor, Cell Proliferation drug effects, Colonic Neoplasms metabolism, Colonic Neoplasms radiotherapy, Colorectal Neoplasms metabolism, Dose-Response Relationship, Drug, Enzyme Inhibitors pharmacology, Gene Expression Regulation drug effects, HT29 Cells, Humans, NF-kappa B metabolism, NF-kappa B radiation effects, Neoplasm Proteins metabolism, Neoplasm Proteins radiation effects, Phosphorylation, Proto-Oncogene Proteins c-akt antagonists & inhibitors, Proto-Oncogene Proteins c-akt metabolism, Rectal Neoplasms metabolism, Rectal Neoplasms radiotherapy, Colorectal Neoplasms radiotherapy, Curcumin pharmacology, NF-kappa B antagonists & inhibitors, Neoplasm Proteins antagonists & inhibitors, Radiation Tolerance physiology, Radiation-Sensitizing Agents pharmacology
- Abstract
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-kappaB (NF-kappaB) 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-kappaB activity in a dose- and time-dependent manner, whereas curcumin suppressed this radiation-induced NF-kappaB activation via inhibition of radiation-induced phosphorylation and degradation of inhibitor of kappaB alpha, inhibition of inhibitor of kappaB kinase activity, and inhibition of Akt phosphorylation. Curcumin also suppressed NF-kappaB-regulated gene products (Bcl-2, Bcl-x(L), inhibitor of apoptosis protein-2, cyclooxygenase-2, and cyclin D1)., Conclusions: Our results suggest that transient inducible NF-kappaB 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.
- Published
- 2009
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