OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.
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-eIF2α-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.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, Richmond, Virginia.
Laurence
L
Booth
Jane L
JL
Roberts
Mehrad
M
Tavallai
Aida
A
Nourbakhsh
John
J
Chuckalovcak
Jori
J
Carter
Andrew
A
Poklepovic
Paul
P
Dent
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001812:Blood-Brain Barrier / Q000187:drug effects*; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D051379:Mice; D018832:Molecular Chaperones / Q000378:metabolism*; D010879:Piperazines / Q000008:administration & dosage; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects; D000068677:Sildenafil Citrate; D013449:Sulfonamides / Q000008:administration & dosage; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; C000717248:Hspa5 protein, mouse; D018832:Molecular Chaperones; C500894:OSU 03012; D010879:Piperazines; D011687:Purines; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D000068677:Sildenafil Citrate