Development of Novel Monocarboxylate Transporter Inhibitors as Potential Anticancer Agents

Abstract

The metabolic phenotype of cancer cells is dependent on the differential oxygen and nutrient distribution in the tumor microenvironment. These diminishing resources coupled with increased energetic and biosynthetic demands of tumor cells further encourage the upregulation of glycolysis with overexpression of related enzymes and transporters. This shift towards a more glycolytic character results in a disruption of the intracellular pH as the cell rapidly becomes more acidic. The accumulation of acidic byproducts like lactic acid requires new strategies to maintain cellular homeostasis resulting in the overexpression of transporters. These extracellular acidic byproducts are taken up by neighboring cells and are utilized for oxidative phosphorylation (OxPhos). Cancer cells often switch between glycolysis and OxPhos to meet the energy demands, termed as metabolic plasticity, which is driven by a necessity to avoid conditions that would induce apoptosis. For this reason, cancer cells express proton coupled monocarboxylate transporters 1-4 (MCT1-4). Specifically, these transporters have been found to be expressed in the most aggressive tumors and ultimately been linked to poor patient outcome. Hence, this transporter can be targeted for therapeutic intervention to treat a wide variety of cancers. One well known MCT1 inhibitor α-cyano-4-hydroxycinnamic acid (CHC) has been traditionally used to study the functions of these transporters and it has been found to reduce tumor growth in mouse xenograft models. The therapeutic potential of CHC is hindered by its lack of efficacy at low concentrations and very high dose requirement for significant anticancer efficacy in vivo. In this regard, we have modified the CHC template with alkyl and aryl silyl substitutions and also introduced nitric oxide donors. These structural modifications have resulted novel candidate compounds which exhibit potent MCT1 and MCT4 inhibition and higher cell proliferation inhibition on several cancer cell lines. These drug candidates have also been evaluated for their effects on glycolytic and mitochondrial metabolic parameters. These studies have shown that all the lead derivatives have significant effects on both metabolic processes. Further in vivo preclinical evaluation of lead candidate compounds indicate that these compounds are generally well tolerated in healthy mice and exhibit growth inhibition in MCT1 and MCT4 expressing tumor models.