Curcumin modulates the radiosensitivity of colorectal cancer cells by suppressing constitutive and inducible NF-kappaB activity.
OBJECTIVE
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
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.
Sandur
Santosh K
SK
Department of Experimental Therapeutics, The University of Texas M D Anderson Cancer Center, Houston, TX 77030, USA.
Deorukhkar
Amit
A
Pandey
Manoj K
MK
Pabón
Ana María
AM
Shentu
Shujun
S
Guha
Sushovan
S
Aggarwal
Bharat B
BB
Krishnan
Sunil
S
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D019073:HT29 Cells; D006801:Humans; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000528:radiation effects; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000528:radiation effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011836:Radiation Tolerance / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D012004:Rectal Neoplasms / Q000378:metabolism / Q000532:radiotherapy
D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009363:Neoplasm Proteins; D011838:Radiation-Sensitizing Agents; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin