Pyrrolidine Dithiocarbamate Enhances the Sensitivity of Oral Squamous Cell Carcinoma Cells Induced by Cisplatin via Inhibiting NF-κB Pathway

Abstract

Background: Understanding the mechanisms underlying chemoresistance is crucial for improving the outcomes of chemotherapy. Nuclear factor κB (NF-κB) signaling can be triggered by a variety of chemotherapeutic drugs and may be involved in the development of tumour resistance. However, its role in oral squamous cell carcinoma (OSCC) resistance to cisplatin (DDP) remains unclear. Here, we sought to investigate it. Methods: OSCC cells were divided into DDP and DDP+pyrrolidine dithiocarbamate (PDTC, an NF-κB inhibitor) groups, and their survival rates as well as the IC50 of DDP were examined after the 5-diphenyltetrazolium bromide solution (MTT) assay. The messenger RNA (mRNA) and protein levels of NF-κB, P-glycoprotein (P-gp), cleaved caspase-3, and B-cell lymphoma/leukaemia-2 (Bcl2) were analysed by reverse transcriptase–polymerase chain reaction (RT-PCR) and western blotting, respectively. Results: The survival rate of OSCC cells and the IC50 of DDP in the DDP+PDTC group were lower than those in the DDP group. Low-dose DDP activated the NF-κB pathway and increased Bcl2 expression in a time-dependent manner, whereas P-gp expression showed no significant changes. PDTC inhibited DDP-induced activation of the NF-κB pathway by upregulating recombinant inhibitory subunit of I Kappa B Alpha (IκBα) expression, which suppressed the expression of the target gene P-gp, resulting in reduced Bcl2 levels and increased caspase-3 activation, ultimately enhancing the sensitivity of OSCC cells to DDP. Conclusion: Low-dose DDP activates NF-κB signalling in OSCC cells, upregulating Bcl2 expression and leading to drug resistance. In contrast, PDTC inhibits NF-κB, which downregulates Bcl2 and P-gp expression and activates caspase-3, enhancing OSCC cell sensitivity to DDP. Our findings suggest that NF-κB signalling plays an important role in the resistance to chemotherapeutic drugs.