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 NaAsO2 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 NaAsO2 alone inhibited aerobic glycolysis (LDHA), it also alleviated autophagy (LC3B) and ROS levels (MDA). DCA improved NaAsO2-dependent inhibition of aerobic glycolysis. CQ addition to arsenite, suppressed autophagy without affecting the Warburg effect. NaAsO2 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 < 0.02; HR (log-rank) = 0.166, CI 95 % 0.03-0.73). This effect was accompanied by a significant increase in mice's mean body weight (p < 0.009). Contrarily to the control, administration of the combo resulted in the absence of progression towards severe dysplasia and OSCC and an overrepresentation of low/mild dysplasia events (100 %). Interestingly, signs of hepatocellular and renal toxicity following combo administration were limited in comparison to control. Taken together, these results suggest that NaAsO2 combined with CQ and DCA may constitute an interesting alternative to eliminating chemo-resistant OSSC tumors by inhibiting aerobic glycolysis and autophagy and controlling ROS generation. In vivo, the drugs may provide a survival advantage by inhibiting tumor development.