Browsing by Subject "Dichloroacetate"

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    DCA and DMAPT as Radiosensitizing Drugs in the Treatment of Pancreatic Cancer
    (Office of the Vice Chancellor for Research, 2013-04-05) Cavazos, Ana; Mendonca, Marc
    Pancreatic cancer is currently one of the deadliest forms of cancer. This is due to high local recurrence and invasiveness. Recurrence is thought to be due in part to the resistance of pancreatic cancer cells. Treatment for pancreatic cancer includes chemotherapy, radiation therapy and surgery. Currently, about 94% of all patients diagnosed with pancreatic cancer die within 5 years of diagnosis. Thus, the focus of this research is to develop a better therapeutic approach to therapy in order to improve the killing of cancer cells and prevent recurrence. We investigated two drugs, Dichloroacetate (DCA) and Dimethylaminoparthenolide (DMAPT, a derivative of Parthenolide). Both DCA and DMAPT were studied for their ability to radiosensitize and help increase radiation induced cell killing in drug treated cancer cells. The experiment involved pancreatic cancer cells (MIA PACA2) being exposed to DMAPT, DCA, and dual treatment, with or without radiation. The cells were then tested for survival rates and doubling times. The hypothesis is that DCA and DMAPT will enhance radiation-induced cell killing of MIA PACA2 cells. The results show that DMAPT and DCA are in fact toxic to the pancreatic cancer cell lines. The dual treatment suppressed cell growth, and increased doubling time of MIA PACA2 cells. Dual treatment also decreased the survival rate of the MIA PACA2 cells (depending on radiation dosage). The data shows that dual treatment of DCA and DMAPT radiation are beneficial in slowing down the spread of pancreatic cancer. Future research will study the mechanisms of radiation sensitization and could help to develop a new technique to treat pancreatic cancer.
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    Pyruvate Dehydrogenase Kinase Is a Metabolic Checkpoint for Polarization of Macrophages to the M1 Phenotype
    (Frontiers, 2019-05-07) Min, Byong-Keol; Park, Sungmi; Kang, Hyeon-Ji; Kim, Dong Wook; Ham, Hye Jin; Ha, Chae-Myeong; Choi, Byung-Jun; Lee, Jung Yi; Oh, Chang Joo; Yoo, Eun Kyung; Kim, Hui Eon; Kim, Byung-Gyu; Jeon, Jae-Han; Hyeon, Do Young; Hwang, Daehee; Kim, Yong-Hoon; Lee, Chul-Ho; Lee, Taeho; Kim, Jung-whan; Choi, Yeon-Kyung; Park, Keun-Gyu; Chawla, Ajay; Lee, Jongsoon; Harris, Robert A.; Lee, In-Kyu; Biochemistry and Molecular Biology, School of Medicine
    Metabolic reprogramming during macrophage polarization supports the effector functions of these cells in health and disease. Here, we demonstrate that pyruvate dehydrogenase kinase (PDK), which inhibits the pyruvate dehydrogenase-mediated conversion of cytosolic pyruvate to mitochondrial acetyl-CoA, functions as a metabolic checkpoint in M1 macrophages. Polarization was not prevented by PDK2 or PDK4 deletion but was fully prevented by the combined deletion of PDK2 and PDK4; this lack of polarization was correlated with improved mitochondrial respiration and rewiring of metabolic breaks that are characterized by increased glycolytic intermediates and reduced metabolites in the TCA cycle. Genetic deletion or pharmacological inhibition of PDK2/4 prevents polarization of macrophages to the M1 phenotype in response to inflammatory stimuli (lipopolysaccharide plus IFN-γ). Transplantation of PDK2/4-deficient bone marrow into irradiated wild-type mice to produce mice with PDK2/4-deficient myeloid cells prevented M1 polarization, reduced obesity-associated insulin resistance, and ameliorated adipose tissue inflammation. A novel, pharmacological PDK inhibitor, KPLH1130, improved high-fat diet-induced insulin resistance; this was correlated with a reduction in the levels of pro-inflammatory markers and improved mitochondrial function. These studies identify PDK2/4 as a metabolic checkpoint for M1 phenotype polarization of macrophages, which could potentially be exploited as a novel therapeutic target for obesity-associated metabolic disorders and other inflammatory conditions.