An O-prenylated benzylidene-thiazolidinedione derivative suppresses NF-κB signaling in a breast cancer cell line: Possible implications for therapy.

Nuclear factor-kappa B (NF-κB), a proinflammatory transcription factor, plays a pivotal role in chemotherapeutic resistance and chemotherapy-induced organ injury. Consequently, combining conventional chemotherapy with an NF-κB inhibitor may optimize therapeutic outcomes by enhancing tumor cell cytotoxicity while mitigating systemic toxicity. In this study, we synthesized a novel thiazolidinedione-based small molecule, O-prenylated benzylidene-thiazolidinedione (PBT), and evaluated its efficacy in combination with cisplatin (CDDP). Ehrlich ascites carcinoma (EAC)-bearing Swiss albino mice received oral PBT (4 mg/kg b.w.,) either alone or in combination with a single intraperitoneal dose of cisplatin (CDDP; 5 mg/kg b.w.,). PBT effectively suppressed NF-κB expression in both tumor cells and renal tissue. PBT effectively inhibited tumor cell proliferation, leading to significant suppression of in vivo tumor growth and prolonged host survival. Mechanistic analysis confirmed that PBT triggered tumor cell apoptosis by upregulating Bax, cytochrome-c, and caspases, while downregulating the anti-apoptotic protein Bcl-2. Furthermore, PBT treatment significantly reduced vascular endothelial growth factor (VEGF) expression and matrix metalloproteinase-9 (MMP-9) levels, underscoring its tumor sensitization potential. Concurrently, PBT attenuated CDDP-induced nephrotoxicity and genotoxicity by modulating inflammatory mediators and antioxidant enzymes. While CDDP monotherapy induced a significant increase (p < 0.05) in chromosomal aberrations and DNA damage in bone marrow cells, PBT co-treatment significantly (p < 0.05) mitigated these genotoxic effects. These findings demonstrate that NF-κB inhibition by PBT represents a promising strategy to improve the efficacy and safety profile of conventional cancer chemotherapy.