OSU-03012 and Viagra Treatment Inhibits the Activity of Multiple Chaperone Proteins and Disrupts the Blood-Brain Barrier: Implications for Anti-Cancer Therapies.

Journal of Cellular Physiology
Laurence BoothPaul Dent

Abstract

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 no...Continue Reading

References

Mar 17, 1999·The American Journal of Cardiology·R M ZusmanI H Osterloh
May 30, 2003·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kwon-Soo HaYoung-Myeong Kim
Jul 16, 2004·Seminars in Oncology·Claus-Henning Koehne, Raymond N Dubois
Mar 10, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Manish I PatelAndrew J Dannenberg
Mar 29, 2005·American Journal of Physiology. Lung Cellular and Molecular Physiology·Bing ZhuTroy Stevens
Jul 27, 2005·Biochemical Society Transactions·K Kashfi, B Rigas
Nov 22, 2005·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Wei CuiKe-Qin Hu
Jan 7, 2006·Cell Death and Differentiation·B He
Nov 26, 2008·American Journal of Physiology. Lung Cellular and Molecular Physiology·Bing ZhuTroy Stevens
Jul 29, 2009·Nitric Oxide : Biology and Chemistry·Andreas Friebe, Doris Koesling
Aug 13, 2010·Molecular & Cellular Proteomics : MCP·Kevin B SpurgersSina Bavari
Apr 6, 2011·Free Radical Biology & Medicine·Lingying TongShiyong Wu
Sep 15, 2011·Cellular Signalling·Lincoln R Potter
Dec 3, 2011·Circulation. Heart Failure·Xiaoyin ShanKenneth B Margulies
Mar 24, 2012·Journal of Cellular Biochemistry·Xiaodong ZhangHeyao Wang
Sep 11, 2012·Archives of Medical Research·Fatemeh Karami-TehraniMorteza Atri
Sep 20, 2012·Cancer Biology & Therapy·Laurence BoothPaul Dent
Oct 16, 2012·The Journal of Biological Chemistry·Mikio KatoMichael E Mendelsohn
Oct 24, 2012·Advances in Cancer Research·Rekha RaoKapil N Bhalla

❮ Previous
Next ❯

Citations

Jul 3, 2015·Clinical & Translational Oncology : Official Publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico·P J VlachostergiosR Daya
Dec 16, 2017·Scientific Reports·Basant A AbdulrahmanHermann M Schatzl
Jul 15, 2016·American Journal of Physiology. Renal Physiology·Kunyu ShenGlenda C Gobe
Jun 16, 2017·Expert Opinion on Investigational Drugs·Matthew W McCarthy, Thomas J Walsh
Jan 16, 2017·Oncotarget·Laurence BoothPaul Dent
Dec 13, 2017·Oncotarget·Ines BaroneStefania Catalano
Sep 16, 2017·The Journal of Infectious Diseases·Matthew W McCarthyThomas J Walsh
Nov 12, 2019·Expert Opinion on Therapeutic Targets·Laurence BoothPaul Dent
Aug 17, 2021·Anti-cancer Drugs·Paul DentJohn F Hancock
Sep 24, 2020·Biochemical Pharmacology·Jonathan O RaynerPaul Dent

❮ Previous
Next ❯

Methods Mentioned

BETA
protein folding
transfection
acetylation

Related Concepts

Related Feeds

Blood Brain Barrier Chips

The blood brain barrier (BBB) is comprised of endothelial cells that regulate the influx and outflux of plasma concentrations. Lab-on-a-chip devices allow scientists to model diseases and mechanisms such as the passage of therapeutic antibodies across the BBB. Discover the latest research on BBB chips here.

Blood Brain Barrier Regulation in Health & Disease

The blood brain barrier is essential in regulating the movement of molecules and substances in and out of the brain. Disruption to the blood brain barrier and changes in permeability allow pathogens and inflammatory molecules to cross the barrier and may play a part in the pathogenesis of neurodegenerative disorders. Here is the latest research in this field.

Blood Brain Barrier

The blood brain barrier is a border that separates blood from cerebrospinal fluid. Discover the latest search on this highly selective semipermeable membrane here.

Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

© 2022 Meta ULC. All rights reserved