Abstract. It has been reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth). Furthermore, omeprazole (OMP) is a well-known agent that enhances the effects of anticancer drugs. The aim of this study was to find clinically-used drugs that enhance the effects of DCA. The combination of DCA and OMP exhibited a more potent antitumor activity than DCA alone in HT1080 fibrosarcoma cells and RKO colon cancer cells, while the drugs did not affect the proliferation of WI-38 human fibroblasts. The inhibitory effect of DCA combined with OMP was reversed with vitamin E and Z-VAD-FMK; therefore conventional caspase-dependent cell growth inhibition through superoxide production was suggested as the mechanism for inhibition. The combination of these drugs also had an effect on HT1080 fibrosarcoma cells inoculated into mice. Since OMP and DCA may be administered orally and have been used clinically for several years without major side effects, we believe that this combination therapy could be readily translated to treat malignant tumors. IntroductionWarburg first observed that even in the presence of sufficient oxygen, cancer cells prefer to metabolize glucose and produce lactic acid (1-4). The concomitant increase in glucose uptake may be exploited clinically for the detection of most solid malignant tumors by fluorodeoxyglucose positron emission tomography (FDG-PET). One possible reason for cancers adopting this less efficient pathway for producing adenosine triphosphate (ATP) compared with oxidative phosphorylation is its advantage for survival and proliferation in the unique hypoxic tumor environment (5). This preference for anaerobic respiration is also considered to be the reason for the resistance cancer cells exhibit to anticancer drugs which induce apoptosis via the mitochondrial pathway. Bonnet et al have reported that treating cancer cells with dichloroacetate (DCA), an approved treatment for congenital lactic acidosis, reverses the Warburg effect and inhibits tumor growth (3,4,(6)(7)(8). DCA increases the flux of pyruvate into the mitochondria by inhibiting the pyruvate dehydrogenase kinase and promotes glucose oxidation over glycolysis. As a result, DCA decreases the production of lactic acid by the tumor and increases the intracellular pH. DCA induces apoptosis via two pathways, one in the mitochondria, where depolarization and superoxide (SOD) production activates mitochondria-dependent apoptosis, and the other at the plasmalemmal level, where activation/upregulation of Kv1.5 channels decreases the (K + )i, activating caspases (6). DCA is a promising anticancer drug due to the convenience of its oral administration, low cost, few side effects and long experience of clinical use (7,8). Although it appeared to be a promising treatment for malignant tumors, its effect is limited in an ongoing report of clinical trials. Therefore, we aimed to find clinically-used drugs that enhance the effects of DCA....

We formerly reported that the combination of dichloroacetate, omeprazole, and tamoxifen blocked cancer progression by reducing lactic acid production and inducing superoxide production. Recently, ivermectin, a well-known anti-parasite drug, was reported to share the same mechanisms with them and have anti-tumor activity. Here, we present three patients in whom the combination of dichloroacetate, omeprazole (plus tamoxifen), and ivermectin dramatically relieved the symptoms accompanying cancer and sarcoma progression.