Browsing by Subject "Arsenic trioxide"
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Item New Mechanism Based Anticancer Drugs for Treatment of Pancreatic and Bladder Cancers(2011-08-08) Jutooru, Indira DeviMethyl 2-cyano-3,11-dioxo-18b-olean-1,12-dien-30-oate (CDODA-Me) is a synthetic triterpenoid that inhibits growth of Panc1 and Panc28 pancreatic cancer cell lines and activates peroxisome proliferator-activated receptor B (PPARB)-dependent transactivation in these cells. CDODA-Me has also induced p21 and p27 protein expression and downregulated cyclin D1; however, these responses were receptor-independent. CDODA-Me induced apoptosis, which was accompanied by receptor-independent induction of the proapoptotic proteins early growth response-1 (Egr-1), nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1), and activating transcription factor-3 (ATF3). Induction of NAG-1 in Panc28 cells was p38-mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3-K)-dependent, but Egr-1-independent, whereas induction in Panc1 cells was associated with activation of p38-MAPK, PI3-K and p42-MAPK and was only partially Egr-1-dependent. Specificity protein (Sp) transcription factors Sp1, Sp3 & Sp4 are overexpressed in multiple tumor types and negative prognostic factors for survival. Since Sp proteins regulate genes associated with survival (survivin), angiogenesis [vascular endothelial growth factor and its receptors] and growth [cyclin D1, epidermal growth factor receptor], research in this laboratory has focused on development of anticancer drugs that decrease Sp protein expression. Arsenic trioxide, curcumin, 2-cyano-3,12-dioxoleana-1,9-dien-28-oic acid (CDDO), CDDO-Me, and celastrol exhibit antiproliferative, antiangiogenic and proapoptotic activity in many cancer cells and tumors. Treatment of cancer cells derived from urologic and gastrointestinal tumors with arsenic trioxide decreased Sp1, Sp3 and Sp4 transcription factors and cotreatment with the proteosome inhibitor MG132 did not inhibit downregulation of Sp proteins in these cancer cells. Mechanistic studies suggested that compound-dependent downregulation of Sp and Sp-dependent genes was due to decreased mitochondrial membrane potential and induction of reactive oxygen species, and the role of peroxides in mediating these responses was confirmed using hydrogen peroxide, demonstrating that the mitochondriotoxic effects of these compounds are important for their anticancer activities. Moreover, repression of Sp and Sp-dependent genes by CDDO-Me and celastrol was due to downregulation of microRNA-27a and induction of ZBTB10, an Sp repressor, and these responses were also reversed by antioxidants. Thus, the anticancer activity of CDDO-Me and celastrol is due, in part, to activation of ROS which in turn targets the microRNA-27a:ZBTB10?Sp transcription factor axis to decrease growth inhibitory, pro-apoptotic and antiangiogenic genes and responses.Item The effects of paraquat and arsenic acid on the growth of distiller's yeast(Texas Tech University, 1982-08) Sullivan, Hanna LowryThe effects of the defoliants arsenic trioxide and paraquat on the growth of Saccharomyces cerevisiae were studied. It was found that 10 and 10 M concentrations of the defoliants did not significantly inhibit the growth of the distiller's yeast, while inhibition -3 -4 -3 was observed at 10 and 10 M concentrations. At 10 M concentrations of both defoliants, the growth of the yeast was inhibited completely in both tryptic soy broth and in a semi-synthetic medium containing glucose as the carbon source. Growth curves revealed an immediate toxic effect on yeasts grown in paraquat-treated media, while the number of viable cells remained constant for a short period of time in media containing arsenic trioxide.