4-hexylresorcinol inhibits NF-κB phosphorylation and has a synergistic effect with cisplatin in KB cells

Cisplatin is a representative anti-cancer drug and 4-hexylresorcinol (4-HR) is known as an antiparasitic and antiseptic agent. The aims of this study were to evaluate the effect of 4-HR on the activation of nuclear factor-κB (NF-κB) in cell cultures, to evaluate the antitumor effect of 4-HR plus cisplatin combination therapy in a xenograft model, and to evaluate transglutaminase-2 (TG-2) and phosphorylated NF-κB (pNF-κB) expression in the xenograft model. To determine the effect of 4-HR on NF-κB phosphorylation, co-immunoprecipitation and Western blot analysis were done in KB cells. To examine the in vivo effect of the cisplatin plus 4-HR combination therapy, KB cells were grafted into nude mice. Drugs were injected into the peritoneal cavity daily. Tumor size, body weight, and duration of survival were checked daily. Specimens from main mass were used in immunohistochemical staining for the analysis of TG-2 and pNF-κB expression. In the in vitro test, as the 4-HR concentrations increased, the fraction of the bound complex NF-κB-inhibitory-κB (IκB) increased. Consequently, the level of free IκB decreased. In the xenograft model, the cisplatin plus 4-HR group exhibited a significantly decreased tumor growth rate than in the saline group (P=0.039). The mean survival time of the cisplatin plus 4-HR group was 51.20±3.96 days and was significantly prolonged compared with the other groups (P<0.05). The body weight of the cisplatin plus 4-HR group had significantly less weight loss than the cisplatin only group (P=0.045). In the immunohistochemical analysis, the cisplatin plus 4-HR group had a significantly lower expression of TG-2 and pNF-κB compared to the saline group (P<0.05). In conclusion, cisplatin plus 4-HR combination therapy had clear advantages over the cisplatin only treatment such as similar tumor growth inhibition compared to the cisplatin only treatment despite the reduced dosage of cisplatin, less body weight loss, and prolonged survival time.