| First Author | Orr WS | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 2 | Pages | e51309 |
| PubMed ID | 23408929 | Mgi Jnum | J:198318 |
| Mgi Id | MGI:5496336 | Doi | 10.1371/journal.pone.0051309 |
| Citation | Orr WS, et al. (2013) Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-kappaB activity. PLoS One 8(2):e51309 |
| abstractText | Ionizing radiation (IR) is an essential component of therapy for alveolar rhabdomyosarcoma. Nuclear factor-kappaB (NF-kappaBeta) transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of curcumin, a putative NF-kappaBeta inhibitor, and cells expressing genetic NF- kappaBeta inhibitors (IkappaBalpha and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-kappaBeta activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-kappaBeta target proteins. Pretreatment of the cells with curcumin inhibited radiation-induced NF-kappaBeta activity and target protein expression. In vivo, the combination of curcumin and IR had synergistic antitumor activity against Rh30 and Rh41 ARMS xenografts. The greatest effect occurred when tumor-bearing mice were treated with curcumin prior to IR. Immunohistochemistry revealed that combination therapy significantly decreased tumor cell proliferation and endothelial cell count, and increased tumor cell apoptosis. Stable expression of the super-repressor, SR-IkappaBalpha, that blocks the classical NF-kappaB pathway, increased sensitivity to IR, while expression of SR-p100, that blocks the alternative pathway, did not. Our results demonstrate that curcumin can potentiate the antitumor activity of IR in ARMS xenografts by suppressing a classical NF-kappaBeta activation pathway induced by ionizing radiation. These data support testing of curcumin as a radiosensitizer for the clinical treatment of alveolar rhabdomyosarcoma. IMPACT OF WORK: The NF-kappaBeta protein complex has been linked to radioresistance in several cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-kappaBeta activity by either pharmacologic (curcumin) or genetic (SR-IkappaBalpha) means significantly enhanced the efficacy of radiation therapy in the treatment of alveolar rhabdomyosarcoma cells and xenografts. These data suggest that preventing the radiation-induced activation of the NF-kappaBeta pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials. |
