Potential Drug Combination With Viagra May Enhance Cancer and Infection Treatments

Paul Dent PhD Massey Cancer Center, Departments of Biochemistry and Molecular Biology Virginia Commonwealth University, Richmond, VA 23298MedicalResearch.com Interview with:
Paul Dent PhD
Massey Cancer Center,
Departments of Biochemistry and Molecular Biology
Virginia Commonwealth University, Richmond, VA 23298

Medical Research: What is the background for this study? What are the main findings?


Dr. Dent: I have worked on understanding how the drug OSU-03012 (AR-12) kills cancer cells since 2005.

The drug was originally advertised as an inhibitor of PDK1 in the PI3 kinase pathway. We found that PDK1 inhibition could not be the major way in which the drug worked. We found that the drug killed brain cancer cells through endoplasmic reticulum stress signaling. And in 2012 we published that OSU-03012 destabilized the chaperone protein GRP78, without significantly altering its transcription. Loss of GRP78 was responsible for the prolonged intense endoplasmic reticulum stress signal, that was toxic. In 2014 we published that OSU-03012 + Viagra / Cialis synergized to kill brain cancer cells. We hypothesized that Viagra / Cialis might enhance the anti-GRP78 effect of OSU-03012; and this was proven to be true.

We discovered that the OSU-03012 + Viagra combination, but not OSU-03012 alone, reduced expression of other chaperone proteins, such as HSP70, GRP94. In mice, the combination was not toxic to “normal” tissues, but was toxic to tumor cells.

In human patients the drug was found to be safe in a phase I trial, with plasma levels of up to 8 microM, and patients on trial for up to 9 months.

Medical Research: What are the main findings?

Dr. Dent: My laboratory is focused on pre-clinical highly applied developmental cancer therapeutics. However, by reading PubMed / National Library of Medicine I discovered that GRP78 was also very important for the replication cycle of many well known viruses. And a homologue of GRP78, called Dna K, is made in bacteria. And Dna K is very important for bacteria; it chaperones the essential protein Rec A.

We discovered that OSU-03012 + Viagra destabilized multiple plasma membrane growth factor receptors, such as EGFR and the IL6-R.

The anti- growth factor receptor effect was blunted by GRP78 over-expression.

We discovered that OSU-03012 + Viagra destabilized multiple plasma membrane virus receptor proteins, such as [NPC1 / TIM1] for Ebola and CAR for coxsakie and adenoviruses.

The anti- virus receptor effect was NOT blocked by GRP78 over-expression.

We discovered that pre-treating cells with OSU-03012 + Viagra significantly reduced the ability of many viruses to infect cells.  After all, we had removed the virus receptors.

We discovered that treatment of virus infected cells with OSU-03012 + Viagra prevented virus reproduction and cell lysis. After all, we had removed GRP78 plus blunted overall chaperone function.

In E coli, antibiotic resistant “superbug” Niesseria gonorrheae, MRSE and MRSA in a dose-dependent fashion stopped their growth and was bacteriocidal. In gonorrheae low concentrations of OSU-03012 restored antibiotic sensitivity. The effects of OSU-03012 were associated with reduced Dna K and Rec A expression.

The take home message is that OSU-03012 + Viagra is a very useful drug combination to reduce GRP78 expression and lower overall chaperone activity in a cell.

Reduced GRP78 and other chaperone function kills brain cancer cells, including stem cell selected variants.

Reduced GRP78 and other chaperone function reduces virus receptor levels in the membrane and stops production of viral proteins in the cell.

Reduced Dna K expression stops bacterial growth, kills superbug bacteria, and makes superbug bacteria sensitive again to standard of care antibiotics.

Medical Research: What should clinicians and patients take away from your report?

Dr. Dent: OSU-03012 has already undergone phase I evaluation in tumor patients.

More work needs to be performed in drug formulation so that consistent drug uptake is obtained.

Once formulation is achieved, it is hoped that OSU-03012 +/- a PDE5 inhibitor could be trialed in glioblastoma and in infectious disease patients

Medical Research: What recommendations do you have for future research as a result of this study?

Dr. Dent: Dent is not a bacteriologist or a virologist. It is for scientists with high knowledge in these fields to take the infectious disease research forwards.

We now know (manuscript submitted to Molecular Cancer Therapeutics) that OSU-03012 + Viagra causes GRP78 down regulation in the normal brain and in the normal liver.

We now know that plasma membrane pumps, ABCB1 and ABCG2, are also down-regulated in vitro and in vivo by our drug combination. ABCB1 and ABCG2 are the two major pumps responsible for the blood-brain-barrier. The our combination not only kills brain cancer cells, but abolishes the blood brain barrier, which will permit entry of other anti-tumor agents.

Dent hopes that if and when OSU-03012 re-enters the clinic he will be able to propose a phase I trial in glioblastoma.

(Dent’s father died of glioblastoma; his mother in law NSCLC; his father in law RCC).

Citation:

GRP78 / BiP / HSPA5 / Dna K is a universal therapeutic target for human disease
Laurence Booth, Jane L. Roberts, Devin R. Cash, Seyedmehrad Tavallai, Sophonie Jean, Abigail Fidanza, Tanya Cruz-Luna, Paul Siembiba, Kelly A. Cycon, Cynthia N. Cornelissen and Paul Dent

Cellular PhysiologyAccepted manuscript online: 24 DEC 2014 05:16AM EST | DOI: 10.1002/jcp.24919