Differential resistance to platinum‐based drugs and 5‐fluorouracil in p22phox‐overexpressing oral squamous cell carcinoma: Implications of alternative treatment strategies

• Published in: Head & neck 2017-08, Vol.39 (8), p.1621-1630
• Main Authors: Hung, Chih‐Chang, Chien, Chen‐Yu, Chu, Pei‐Yu, Wu, Yu‐Jen, Lin, Chang‐Shen, Huang, Chih‐Jen, Chan, Leong‐Perng, Wang, Yen‐Yun, Yuan, Shyng‐Shiou F., Hour, Tzyh‐Chyuan, Chen, Jeff Yi‐Fu
• Format: Article
• Language: English
• Subjects: 5-Fluorouracil; Animals; Apoptosis; Apoptosis - drug effects; Carboplatin; Carboplatin - therapeutic use; Carcinoma, Squamous Cell - drug therapy; Carcinoma, Squamous Cell - metabolism; Cell Line, Tumor; Chemoresistance; Chemotherapy; Cisplatin; Cisplatin - therapeutic use; Cytotoxicity; differential resistance; Drug resistance; Drug Resistance, Neoplasm; Fluorouracil - therapeutic use; Head and neck; Humans; Immunoblotting; Mice; Mouth Neoplasms - drug therapy; Mouth Neoplasms - metabolism; NADPH Oxidases - metabolism; Oral cancer; Oral squamous cell carcinoma; Organoplatinum Compounds - therapeutic use; Oxaliplatin; p22phox; Platinum; Platinum Compounds - therapeutic use; platinum‐based drugs; Squamous cell carcinoma; Tumors; Up-Regulation; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 1043-3074; 1097-0347
• DOI: 10.1002/hed.24803

Background We have previously shown that p22phox confers resistance to cisplatin in oral squamous cell carcinoma (OSCC). Whether p22phox has clinical correlation with cisplatin resistance and affects the efficacy of other platinum or nonplatinum drugs is unknown. Methods The p22phox expression in tissues and apoptotic markers in cell lines was detected by immunoblotting. The cytotoxicity of chemotherapy drugs was determined by methylthiazol tetrazolium assay. In vivo chemoresistance of p22phox‐overexpressing tumors was confirmed by the xenograft mouse model. Results The p22phox was upregulated in tumors of patients with OSCC refractory to cisplatin treatment. The p22phox overexpression markedly increased the resistance to cisplatin and carboplatin, but not oxaliplatin and 5‐fluorouracil (5‐FU), in OSCC cells by differentially inhibiting the drug‐induced apoptosis. Furthermore, p22phox‐dependent resistance to cisplatin, but not 5‐FU, was demonstrated in mouse xenograft tumors. Conclusion The p22phox expression may not only be a prognostic biomarker for prediction of chemotherapy outcomes, but the indication for alternative treatment strategies in oral cancer.