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New drug combination in preclinical laboratory studies effectively kills brain and breast cancer, and inhibits Ebola, influenza and many other viruses and superbug bacteria

Drugs interact with a protein that could be a universal therapeutic target for cancer and infectious diseases

Paul Dent for blog
Paul Dent, Ph.D.

Scientists at Virginia Commonwealth University Massey Cancer Center have developed a drug combination that kills brain and breast cancer stem cells in preclinical laboratory studies. The breakthrough drug combination also prevents viruses, including Ebola, from replicating and makes “superbug” bacteria vulnerable to common antibiotics. The combination works by targeting a protein known as GRP78, according to a study published in the Journal of Cellular Physiology.

By using a drug combination of the clinically tested OSU-03012 (AR-12) and FDA-approved phosphodiesterase  5 inhibitors (such as Viagra and Cialis) to target GRP78 and related proteins, researchers killed brain cancer cells and their stem cells, killed breast cancer cells, prevented the replication of a variety of major viruses in infected cells and made antibiotic-resistant bacteria vulnerable to antibiotics again. Data were obtained in multiple brain cancer stem cell types, breast cancer cells and using influenza, mumps, measles, Chikungunya, Ebola, hepatitis, E. coli, MRSA, MRSE and N. gonorrhoeae, among others.

“Basically, we’ve got a concept that by attacking GRP78 and related proteins: (a) we hurt cancer cells; (b) we inhibit the ability of viruses to infect and to reproduce; and (c) we are able to kill superbug antibiotic-resistant bacteria,” said the study’s lead investigator, Paul Dent, Ph.D., Universal Corporation Chair in Cancer Cell Signaling and member of the Developmental Therapeutics research program at VCU Massey Cancer Center.

GRP78 is part of a family of proteins called chaperones. The job of a chaperone is to help shape chains of amino acids into proteins and then to keep those proteins active in the correct 3D shape. Chaperone proteins are very important in cancer cells or virus-infected cells because these cells make extra protein compared to normal/uninfected cells. The OSU/Viagra drug combination attacks GRP78 and other chaperones, thereby killing cancer cells. The team found that the drug combination also reduced the expression of oncogene receptors in cancer cells.

After learning of the drug combination’s effect on GRP78 in cancer cells, Dent and his team began to target GRP78 for infectious diseases causing viruses and bacteria.  The team found that the OSU/Viagra drug combination inhibited virus infectivity by reducing viral receptor levels on the surface of target cells and also the prevention of virus replication in infected cells. In bacteria, the OSU drug as a single agent reduced expression of the equivalent GRP78 protein, in bacteria called Dna K, and induced cell death in pan-antibiotic resistant forms of E. coli, MRSE, MRSA and N. gonorrhoeae.

“The findings open an avenue of being able to treat viral infections; infections that so far do not have adequate treatments. We’ve proved that GRP78 is a ‘drugable’ target to stop viruses from reproducing and spreading in the laboratory,” Dent said. “And in the case of bacteria, we have a new antibiotic target, Dna K, that if we’re careful and only use the OSU drug for the most resistant bacteria, we’ve got something that may help to treat the so-called superbugs.

Dent said that the next steps have already been taken and are leading to new discoveries: “We know in mice that the OSU/Viagra treatment can kill transplanted tumor cells but doesn’t harm normal tissues like the liver and the heart. Of even more importance, we’ve just discovered that the OSU/Viagra combination can reduce the levels of proteins known as “pumps” in the mouse brain and liver. Pumps are responsible for making tumor cells resistant to chemotherapy and for stopping brain cancer chemotherapy from entering into the brain and killing cancer cells.”

This study was supported by VCU Massey Cancer Center as well as National Institutes of Health (NIH) grants U19AI31496 and F30AI112199 and, in part, by Massey’s National Cancer Institute Cancer Center Support Grant P30 CA016059.

The full article is available online at http://onlinelibrary.wiley.com/doi/10.1002/jcp.24919/abstract

Written by: John Wallace

Posted on: October 22, 2015

Category: Research