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 workThe 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.

Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma

“…Curcumin (diferuloylmethane), a hydrophobic polyphenol molecule extracted from turmeric (Curcuma longa Linn), has a wide range of pharmacological activities, including anti-inflammatory, antioxidant and anticancer properties (9). Curcumin exerts a suppressive effect on NF-κB activity in various biological contexts (10,11). For instance, curcumin has been found to enhance the chemosensitization of colorectal cancer cells to conventional chemotherapeutic agents, such as 5-fluorouracil through inhibition of NF-κB and Src protein kinase signaling pathways (10).…”

[6]-Gingerol enhances the radiosensitivity of gastric cancer via G2/M phase arrest and apoptosis induction

“…Therefore, searching for new radiosensitizers is of great importance. Phytochemicals have drawn wide attention as promising radiosensitizers in the course of radiotherapy (20)(21)(22)(23). [6]-Gingerol has demonstrated potential chemopreventive ability in various cancer types.…”

Paeonol enhances the sensitivity of human ovarian cancer cells to radiotherapy-induced apoptosis due to downregulation of the phosphatidylinositol-3-kinase/Akt/phosphatase and tensin homolog pathway and inhibition of vascular endothelial growth factor

“…Understanding the mechanisms and the signaling pathways associated with regulation of resistance to radiation is crucial in development of approaches to overcome this. Previous research has focused on identifying tumor-specific sensitizing agents to enhance radiotherapy, and multiple studies have demonstrated the effect of many natural compounds, including curcumin and berberine, in improving sensitivity of cancer cells to radiation (31)(32)(33). A previous study has also reported the antitumor effects of paeonol on human lung adenocarcinoma cells (34).…”