Browsing by Subject "CHC"
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Item Development of Novel Monocarboxylate Transporter Inhibitors as Potential Anticancer Agents(2019-04) Nelson, GradyThe 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.Item Novel Monocarboxylate Transporter 1 and 4 Inhibitors: In Vitro and In Vivo Studies as Potential Anticancer Agents(2019-04) Jonnalagadda, ShirishaThe primary goal of my research project is to develop novel drug candidates that target cancer cell glycolysis and oxidative phosphorylation via MCT1 and/or MCT4 inhibition for the treatment of cancers. We have discovered several candidate compounds based on CHC and coumarin templates with low nanomolar potency. The current research is innovative because the compounds presented in this thesis are among the very first to be used as dual monocarboxylate transporters 1 and 4 inhibitors (MCT1 and MCT4) for cancer treatment. These dual MCT1 and MCT4 inhibitors have low cell proliferation inhibition and are well tolerated in mice at high dosages. These inhibitors have been tested in in vivo tumor models and these studies indicate significant tumor growth inhibition in MCT1 expressing WiDr, 4T1-luc2 and GL261-luc2 and MCT4 expressing MDA-MB-231 xenograft/syngraft models. Our recently discovered highly potent dual MCT1 and MCT4 inhibitors are easy to synthesize, generally non-toxic, water soluble, and effective in arresting the tumor growth in vivo as single agents as well as in combination with clinical drugs. The impact of this project will be an enhanced, and improved anticancer agents and a longer and better quality of life for cancer patients with MCT1 and/or MCT4 expressing cancers. As MCT1 and/or MCT4 are expressed in a wide variety of cancers, these inhibitors can also be used as a broad-spectrum anticancer agents for the treatment of solid tumors.