Ionizing radiation (IR) is an essential component of
therapy for
alveolar rhabdomyosarcoma.
Nuclear factor-kappaB (NF-κΒ)
transcription factors are upregulated by IR and have been implicated in radioresistance. We evaluated the ability of
curcumin, a putative NF-κΒ inhibitor, and cells expressing genetic NF- κΒ inhibitors (IκBα and p100 super-repressor constructs) to function as a radiosensitizer. Ionizing radiation induced NF-κΒ activity in the ARMS cells in vitro in a dose- and time-dependent manner, and upregulated expression of NF-κΒ target
proteins. Pretreatment of the cells with
curcumin inhibited radiation-induced NF-κΒ 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-IκBα, that blocks the classical NF-κB 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-κΒ 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-κΒ
protein complex has been linked to radioresistance in several
cancers. In this study, we have demonstrated that inhibiting radiation-induced NF-κΒ activity by either pharmacologic (
curcumin) or genetic (SR-IκBα) 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-κΒ pathway is a promising way to improve the antitumor efficacy of ionizing radiation and warrants clinical trials.