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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 J+Cell+Physiol
2015 ; 230
(8
): 1982-98
Nephropedia Template TP
gab.com Text
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English Wikipedia
OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone
Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer
Therapies
#MMPMID25736380
Booth L
; Roberts JL
; Tavallai M
; Nourbakhsh A
; Chuckalovcak J
; Carter J
; Poklepovic A
; Dent P
J Cell Physiol
2015[Aug]; 230
(8
): 1982-98
PMID25736380
show ga
We examined the interaction between OSU-03012 (also called AR-12) with
phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone
glucose-regulated protein (GRP78)/BiP/HSPA5 in the cellular response. Sildenafil
(Viagra) interacted in a greater than additive fashion with OSU-03012 to kill
stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the
expression of multiple oncogenic growth factor receptors and plasma membrane drug
efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90
family chaperone proteins. Decreased expression of plasma membrane receptors and
drug efflux pumps was dependent upon enhanced PERK-eIF2?-ATF4-CHOP signaling and
was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more
efficacious than treatment with celecoxib and sildenafil at killing tumor cells
without damaging normal tissues and in parallel reduced expression of ABCB1 and
ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized
with low concentrations of sorafenib to kill tumor cells, and with lapatinib to
kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human
tumor tissue from an OSU-03012/sildenafil treated mouse, we noted a profound
reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers
for potentially suppressing the killing response. Inhibition of FGFR signaling
and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil
lethality.