New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists

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Title: New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists
Author: Chintharlapalli, Sudhakar Reddy
Abstract: 1 ,1 -Bis (3' -indolyl ) -1 - (p -substitutedphenyl )methanes containing ptrifluoromethyl (DIM -C -pPhCF3 ) , p -t -butyl (DIM -C -pPhtBu ) , and phenyl (DIM -CpPhC6H5 ) substituents have been identified as a new class of peroxisome proliferatoractivated receptor ? ? ? ? (PPAR ? ? ? ? ) agonists that exhibit antitumorigenic activity . In this study , the PPAR ? ? ? ? -active compounds decreased HT -29 , HCT -15 , RKO , HCT116 and SW480 colon cancer cell survival and KU7 and 253JB -V33 bladder cancer cell survival . In HT - 29 , HCT -15 , SW480 and KU7 cells , the PPAR ? ? ? ? agonists induced caveolin -1 expression and this induction was significantly downregulated after cotreatment with the PPAR ? ? ? ? antagonist GW9662 . Since overexpression of caveolin -1 is known to suppress cancer cell and tumor growth , the growth inhibitory effects of the DIM compounds in these cell lines are associated with PPAR ? ? ? ? -dependent induction of caveolins . These PPAR ? ? ? ? -active compounds did not induce caveolin -1 in HCT -116 cells . However , these compounds induced NSAID -activated gene -1 (NAG -1 ) and apoptosis in this cell line . This represents a novel receptor -independent pathway for C -DIM -induced growth inhibition and apoptosis in colon cancer cells . In SW480 colon cancer cells 2 .5 -7 .5 ? ? ? ?M C -DIMs induced caveolin -1 whereas high concentrations (10 ? ? ? ?M ) induced pro -apoptotic NAG -1 expression . In athymic nude mice bearing SW480 cell xenografts DIM -C -pPhC6H5 inhibited tumor growth and immunohistochemical staining of the tumors show induction of apoptosis and NAG -1 expression . Thus , the PPAR ? ? ? ? -active compounds induce both receptor -dependent and -independent responses in SW480 cells which are separable over a narrow range of concentrations and this dual mechanism of action enhances their antiproliferative and anticancer activities . Similar results were obtained for another structural class of PPAR ? ? ? ? agonists namely 2 -cyano -3 ,12 -dioxoolean -1 ,9 -dien -28 -oic acid (CDDO ) and the corresponding methyl (CDDO -Me ) and imidazole (CDDO -Im ) esters . Structure -activity studies show that 1 ,1 -bis (3' -indolyl ) -1 - (psubstitutedphenyl ) methanes containing p -trifluoromethyl (DIM -C -pPhCF3 ) , hydrogen (DIM -C -pPh ) and p -methoxy (DIM -C -pPhOCH3 ) substituents activate Nur77 and induce apoptosis in pancreatic , prostate , and breast cancer cell lines . Nur77 agonists activate the nuclear receptor , and downstream responses include decreased cell survival , induction of cell death pathways including tumor necrosis factor related apoptosis -inducing ligand (TRAIL ) and PARP cleavage . Nur77 agonists also inhibit tumor growth in vivo in athymic nude mice bearing Panc -28 cell xenografts .
URI: http : / /hdl .handle .net /1969 .1 /5978
Date: 2007-09-17

Citation

New mechanism-based anticancer drugs that act as orphan nuclear receptor agonists. Available electronically from http : / /hdl .handle .net /1969 .1 /5978 .

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