Investigation of the mechanisms involved in radiosensitization of squamous carcinoma cells by the chemopreventive agent curcurmin

Radiation therapy is employed in the treatment of many cancers. As beneficial as radiation therapy is for tumor control, there exists a limit to the dose and frequency with which patients receive radiation, due to the sensitivity of normal tissues. Moreover, many tumor cells are able to withstand the damage caused by radiation and continue to proliferate. For treatment of these radioresistant tumors, such as cervical and head & neck cancers, development of radiosensitizers with low systemic toxicity is an active area of research.Here we report that curcumin, a naturally occurring plant polyphenol, is a potent radiosensitizer of tumor but not normal, untransformed cells. Irradiation of tumor cells in the presence of curcumin leads to an increased production of reactive oxygen species (ROS) and sustained MAP kinase activation. Both these effects are required for radiosensitization by curcumin, as ROS scavengers like N-acetyl-cysteine and MAP kinase inhibitors block curcumin-mediated radiosensitization. Moreover, our studies revealed that the differential radiosensitization of tumor and normal cells by curcumin is likely due to inhibition of a key anti-oxidant redox enzyme, thioredoxin reductase-1 (TxnRd1), which is significantly overexpressed in tumor cells and tissues.Our findings identify TxnRd1 as a critical mediator of curcumin-induced radiosensitization. Studies are under way to test these findings in vivo, using an orthotopic mouse tumor model. Positive results from these studies will establish TxnRd1 as a potential marker in clinical clinical trials with curcumin and ionizing radiation. Moreover, since other bioactive dietary components (e.g., caffeic acid phenethyl ester, oleocanthol) with similar structural motifs as curcumin have the potential to inhibit TxnRd1 activity, these results could have implication in radiosensitization by these classes of compounds as well. Curcumin is a relatively inexpensive and abundant compound with demonstrated safety, but has not been previously been tested as a radiosensitizer in the clinic. In vitro and in vivo results from our study could have immediate translational potential in to starting a clinical trial with curcumin as a radiosensitizer.