Dichloroacetate and chloroquine in combination with arsenite suppress ROS-induced oral squamous cell carcinoma (OSCC) development and improve BALB/c mice survival

Oral squamous cell carcinoma (OSCC) is a disabling tumor with poor response to chemotherapy. Here, we sought to explore a new chemotherapeutic approach based on a combined induction of cytotoxic ROS and targeting of autophagy and aerobic glycolysis as central contributors to OSCC carcinogenesis and chemoresistance. To this end, tongue OSCC was generated in BALB/c mice using 4NQO. Treatment of mouse-derived OSSC explants with NaAsO resulted in a strong inhibition of MTT activity and Bcl-2 and Ki-67 expression. The addition of chloroquine (CQ) and dichloroacetate (DCA) to arsenite, resulted in additive inhibitory effects on Bcl-2 and Ki-67 expression. Whereas NaAsO alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO -dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO combination with CQ and DCA improved the oxidative status balance by boosting anti-oxidative CAT and SOD and controlling pro-oxidant MDA activity. The administration of the combo to 4NQO-mice resulted in a significant survival advantage over the control group (90 % vs. 35 % survival at week 32, p