• 4/3/2008
  • Houston, TX
  • Ajaikumar B. Kunnumakkara et al.
  • linical Cancer Research 14, 2128-2136, April 1, 2008

Curcumin Sensitizes Human Colorectal Cancer Xenografts in Nude Mice to {gamma}-Radiation by Targeting Nuclear Factor-{kappa}B–Regulated Gene Products

Purpose:
How colorectal cancer develops resistance to {gamma}-radiation is not fully understood, but the transcription factor nuclear factor-{kappa}B (NF-{kappa}B) and NF-{kappa}B–regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-{kappa}B activation, whether it can sensitize the colorectal cancer to {gamma}-radiation was investigated in colorectal cancer xenografts in nude mice.

Experimental Design:
We established HCT 116 xenograft in nude mice, randomized into four groups, and treated with vehicle (corn oil), curcumin, {gamma}-radiation, and curcumin in combination with {gamma}-radiation. NF-{kappa}B modulation was ascertained using electrophoretic mobility shift assay and immunohistochemistry. Markers of proliferation, angiogenesis, and invasion were monitored by immunohistochemistry and Western blot analysis.

Results:
Curcumin significantly enhanced the efficacy of fractionated radiation therapy by prolonging the time to tumor regrowth (P = 0.02) and by reducing the Ki-67 proliferation index (P < 0. 001). Moreover, curcumin suppressed NF-{kappa}B activity and the expression of NF-{kappa}B–regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase-9, and vascular endothelial growth factor), many of which were induced by radiation therapy and mediate radioresistance. The combination of curcumin and radiation therapy also suppressed angiogenesis, as indicated by a decrease in vascular endothelial growth factor and microvessel density (P = 0.002 versus radiation alone).

Conclusion:
Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-{kappa}B and NF-{kappa}B–regulated gene products, leading to inhibition of proliferation and angiogenesis.

Authors:
Ajaikumar B. Kunnumakkara1, Parmeswaran Diagaradjane2, Sushovan Guha3, Amit Deorukhkar2, Shujun Shentu2, Bharat B. Aggarwal1 and Sunil Krishnan2

Authors’ affiliations:
Departments of 1 Experimental Therapeutics, 2 Radiation Oncology, and 3 Gastroenterology, Hepatology and Nutrition, The University of Texas M. D. Anderson Cancer Center, Houston, Texas