title: Curcumin potentiates rhabdomyosarcoma radiosensitivity by suppressing NF-κB activity.
abstract: 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.
authors: University of Tennessee Health Science Center, Department of Surgery, Memphis, Tennessee, USA.
authors: W Shannon
authors: WS
authors: Orr
authors: Jason W
authors: JW
authors: Denbo
authors: Karim R
authors: KR
authors: Saab
authors: Catherine Y
authors: CY
authors: Ng
authors: Jianrong
authors: J
authors: Wu
authors: Kui
authors: K
authors: Li
authors: Jo Meagan
authors: JM
authors: Garner
authors: Christopher L
authors: CL
authors: Morton
authors: Ziyun
authors: Z
authors: Du
authors: Lawrence M
authors: LM
authors: Pfeffer
authors: Andrew M
authors: AM
authors: Davidoff
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003474:Curcumin / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism*; D011836:Radiation Tolerance; D011839:Radiation, Ionizing; D018232:Rhabdomyosarcoma, Alveolar / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; D003474:Curcumin