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

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

Requests for reprints: Sunil Krishnan, Box 97, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-563-2377; E-mail: skrishnan{at}mdanderson.org or Bharat B. Aggarwal, Box 143, M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-794-1817; Fax: 713-745-6339; Email: aggarwal{at}mdanderson.org.

Purpose: How colorectal cancer develops resistance to -radiation is not fully understood, but the transcription factor nuclear factor-B (NF-B) and NF-B–regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-B activation, whether it can sensitize the colorectal cancer to -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, -radiation, and curcumin in combination with -radiation. NF-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-B activity and the expression of NF-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-B and NF-B–regulated gene products, leading to inhibition of proliferation and angiogenesis.