Browsing by Subject "glycolysis"

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    Effects of oxygen availability on metabolic enzyme abundances in Leptomonas pyrrhocoris
    (2024-04-26) Tangen, Madelyn R
    Trypanosomes are parasitic protozoans. Trypanosomes have a unique membrane-bound metabolic organelle called the glycosome, which contains the first seven steps of glycolysis. It is thought the glycosome formed to facilitate enzymatic overhauls that were cellular responses to altered environmental conditions. Environmental changes are more apparent for dual-host trypanosomes, but the glycosome is still found in single-host species. This led to the research question: In single-host trypanosomes, what environmental condition could potentially cause glycosomal protein abundance changes? We hypothesized that a dramatic change in oxygen levels is responsible for the overhaul of glycosomal enzymes in the single-host trypanosome species Leptomonas pyrrhocoris. Additionally, this overhaul would not be seen in metabolic enzymes located outside the glycosome. To test the hypothesis, Leptomonas pyrrhocoris cells were placed in hypoxia and normoxia conditions. Cell counting and protein collection occurred on days two, three, and six. The abundances of five glycosomal enzymes and one cytoplasmic enzyme were measured via western blotting. Significance was determined through an unpaired two-tailed t-test. Trends observed in all enzymes showed that by day three enzymatic abundance was greater in hypoxia. This trend was either maintained or amplified through day six in all but one enzyme. However, because this trend was also observed in the cytosolic enzyme, the hypothesis was rejected. The trend seen in all enzymes suggests that while a change in oxygen level does cause an enzymatic overhaul, it is not one related to the glycosome.
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    Novel Monocarboxylate Transporter 1 and 4 Inhibitors: In Vitro and In Vivo Studies as Potential Anticancer Agents
    (2019-04) Jonnalagadda, Shirisha
    The 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.