Year: 2013
Type: dissertation
Abstract: Curcumin is the active component of tumeric, and this polyphenolic\ncompound has been extensively investigated as an anticancer drug that\nmodulates multiple pathways and genes. We demonstrated that curcumin\ninhibited 253JB-V and KU7 bladder cancer cell growth, and this was\naccompanied by induction of apoptosis and decreased expression of the\nproapoptotic protein survivin and the angiogenic proteins vascular endothelial\ngrowth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of\nsurvivin, VEGF and VEGFR1 are dependent on specificity protein (Sp)\ntranscription factors, we also investigated the effects of curcumin on\ndownregulation of Sp protein expression as an underlying mechanism for the\napoptotic and antiangiogenic activity of this compound. Curcumin decreases\nexpression of Sp1, Sp3 and Sp4 in blader cancer cells indicating that the cancer\nchemotherapeutic activity of curcumin is due, in part, to decreased expression of\nSp transcription factors and Sp-dependent genes. Betulinic acid (BA) and\ncurcumin are phytochemical anticancer agents, and we hypothesized that both\ncompounds decrease EGFR expression in bladder cancer through\ndownregulation of specificity protein (Sp) transcription factors. BA and curcumin\ndecreased expression of EGFR, Sp1, Sp3, Sp4 and Sp-dependent proteins in\n253JB-V and KU7 cells; EGFR was also decreased in cells transfected with a\ncocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3 and Sp4 showing\nthat EGFR is an Sp-regulated gene. Methyl 2-cyano-3,11-dioxo-18?-olean-1,12-\ndien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid which inhibits proliferation of KU7 and 253JB-V bladder cancer cells.\nCDODA-Me also decreased expression of specificity protein-1 (Sp1), Sp3 and\nSp4 transcription factors. Similar results were observed for a structurally-related\ntriterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me),\nwhich is currently in clinical trials for treatment of leukemia. Celastrol, a naturally\noccurring triterpenoid acid from an ivy-like vine exhibits anticancer activity\nagainst bladder cancer cells. Celastrol decreased cell proliferation, induced\napoptosis and decreased expression of specificity protein (Sp) transcription\nfactors Sp1, Sp3 and Sp4 and several Sp-dependent genes like Fibroblast\ngrowth factor receptor 3 (FGFR3). In vivo studies using KU7 cells as xenografts\nshowed that celastrol represents novel class of anticancer drugs that acts, in\npart, through targeting downregulation of Sp transcription factors.
Author: Gayathri Chadalapaka
Language: English
Subfield: Molecular Medicine
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2612704950