NF-κB Inhibitors as Radiosensitizers

Cancer remains a formidable challenge, demanding innovative therapeutic strategies to overcome limitations of current multimodal treatments, including cost, side effects, and primary resistance, particularly to immunotherapy. The nuclear factor-kappa B (NF-κB) signaling pathway, a key regulator of tumor immunosuppression and cellular survival, plays a critical role in cancer initiation, progression, and treatment resistance. Notably, NF-κB activation by ionizing radiation (IR) often leads to radioresistance, highlighting the potential of NF-κB inhibition to enhance radiotherapy efficacy. Curcumin, a known NF-κB inhibitor, suffers from poor bioavailability, limiting its clinical application. However, our in-house synthesized curcumin analogs (PACs), including PAC-CH3, PAC-NH, PAC-Ethoxy, and PAC-Pt, demonstrate promising improvements in solubility and NF-κB inhibition. This study aims to investigate the radiosensitizing potential of these novel PACs in breast cancer cell lines (MCF-7, MDA-MB-231) and normal cells. We hypothesize that combining PACs with radiation will enhance tumor cell killing by inhibiting NF-κB and anti-apoptotic Bcl-2, while promoting pro-apoptotic p53 and BAX pathways. To test this, we will assess cell viability, apoptosis induction, and the expression of key molecules (NF-κB, p53, Bax, Bcl-2) using Real-Time PCR and Western blotting. Clonogenic survival assays will determine the efficacy of the combined therapies. This research will provide critical insights into the potential of PACs as radiosensitizers, potentially leading to more effective and less toxic cancer treatments and improved patient outcomes.

Basem Alotaibi.