Curcumin sensitizes human colorectal cancer xenografts in nude mice to gamma-radiation by targeting nuclear factor-kappaB-regulated gene products.
OBJECTIVE
How colorectal cancer develops resistance to gamma-radiation is not fully understood, but the transcription factor nuclear factor-kappaB (NF-kappaB) and NF-kappaB-regulated gene products have been proposed as mediators. Because curcumin, a component of turmeric (Curcuma longa), has been shown to suppress NF-kappaB activation, whether it can sensitize the colorectal cancer to gamma-radiation was investigated in colorectal cancer xenografts in nude mice.


METHODS
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-kappaB 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-kappaB activity and the expression of NF-kappaB-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).


CONCLUSIONS
Collectively, our results suggest that curcumin potentiates the antitumor effects of radiation therapy in colorectal cancer by suppressing NF-kappaB and NF-kappaB-regulated gene products, leading to inhibition of proliferation and angiogenesis.
Kunnumakkara
Ajaikumar B
AB
Department of Experimental Therapeutics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Diagaradjane
Parmeswaran
P
Guha
Sushovan
S
Deorukhkar
Amit
A
Shentu
Shujun
S
Aggarwal
Bharat B
BB
Krishnan
Sunil
S
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D003474:Curcumin / Q000494:pharmacology*; D024202:Electrophoretic Mobility Shift Assay; D005720:Gamma Rays; D015870:Gene Expression / Q000187:drug effects*; D006801:Humans; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D019394:Ki-67 Antigen; D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; D003474:Curcumin