Curcumin is the active component of tumeric, and this polyphenolic
compound has been extensively investigated as an anticancer drug that
modulates multiple pathways and genes. We demonstrated that curcumin
inhibited 253JB-V and KU7 bladder cancer cell growth, and this was
accompanied by induction of apoptosis and decreased expression of the
proapoptotic protein survivin and the angiogenic proteins vascular endothelial
growth factor (VEGF) and VEGF receptor 1 (VEGFR1). Since expression of
survivin, VEGF and VEGFR1 are dependent on specificity protein (Sp)
transcription factors, we also investigated the effects of curcumin on
downregulation of Sp protein expression as an underlying mechanism for the
apoptotic and antiangiogenic activity of this compound. Curcumin decreases
expression of Sp1, Sp3 and Sp4 in blader cancer cells indicating that the cancer
chemotherapeutic activity of curcumin is due, in part, to decreased expression of
Sp transcription factors and Sp-dependent genes. Betulinic acid (BA) and
curcumin are phytochemical anticancer agents, and we hypothesized that both
compounds decrease EGFR expression in bladder cancer through
downregulation of specificity protein (Sp) transcription factors. BA and curcumin
decreased expression of EGFR, Sp1, Sp3, Sp4 and Sp-dependent proteins in
253JB-V and KU7 cells; EGFR was also decreased in cells transfected with a
cocktail (iSp) containing small inhibitory RNAs for Sp1, Sp3 and Sp4 showing
that EGFR is an Sp-regulated gene. Methyl 2-cyano-3,11-dioxo-18?-olean-1,12-
dien-30-oate (CDODA-Me) is a synthetic triterpenoid derived from glycyrrhetinic acid which inhibits proliferation of KU7 and 253JB-V bladder cancer cells.
CDODA-Me also decreased expression of specificity protein-1 (Sp1), Sp3 and
Sp4 transcription factors. Similar results were observed for a structurally-related
triterpenoid, methyl 2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me),
which is currently in clinical trials for treatment of leukemia. Celastrol, a naturally
occurring triterpenoid acid from an ivy-like vine exhibits anticancer activity
against bladder cancer cells. Celastrol decreased cell proliferation, induced
apoptosis and decreased expression of specificity protein (Sp) transcription
factors Sp1, Sp3 and Sp4 and several Sp-dependent genes like Fibroblast
growth factor receptor 3 (FGFR3). In vivo studies using KU7 cells as xenografts
showed that celastrol represents novel class of anticancer drugs that acts, in
part, through targeting downregulation of Sp transcription factors.
| Identifer | oai:union.ndltd.org:tamu.edu/oai:repository.tamu.edu:1969.1/148439 |
| Date | 14 March 2013 |
| Creators | Chadalapaka, Gayathri |
| Contributors | Safe, Stephen H |
| Source Sets | Texas A and M University |
| Detected Language | English |
| Type | Thesis, text |
| Format | application/pdf |
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