Cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) reduces survival.In this study we hypothesized that methylation of key genes mediates cisplatin resistance.We determined whether a demethylating drug, decitabine, could augment the anti-proliferative and apoptotic effects of cisplatin on SCC-25/CP, a cisplatin-resistant tongue SCC cell line.We showed that decitabine treatment restored cisplatin sensitivity in SCC-25/CP and significantly reduced the cisplatin dose required to induce apoptosis.
We then created a xenograft model with SCC-25/CP and Bumpers determined that decitabine and cisplatin combination treatment resulted in significantly reduced tumor growth and mechanical allodynia compared to control.To establish a gene classifier we quantified methylation in cancer tissue of cisplatin-sensitive and cisplatin-resistant HNSCC patients.Cisplatin-sensitive and cisplatin-resistant patient tumors had distinct methylation profiles.When we quantified methylation and expression of genes in the classifier in HNSCC cells in vitro, we showed that decitabine treatment of cisplatin-resistant HNSCC cells reversed methylation and gene expression toward a cisplatin-sensitive profile.
The study provides direct evidence that decitabine restores cisplatin sensitivity in in vitro MAGNESIUM BIS-GLYCINATE 300 ULTRA GENTLE and in vivo models of HNSCC.Combination treatment of cisplatin and decitabine significantly reduces HNSCC growth and HNSCC pain.Furthermore, gene methylation could be used as a biomarker of cisplatin-resistance.