A research team led by scientists at Virginia Commonwealth University reports that a protein called GRP78 could be a universal therapeutic target for treating human diseases such as brain cancer, Ebola, Influenza, hepatitis, and superbug bacteria such as MRSE and MRSA. The preclinical study, “GRP78/BiP/HSPA5/Dna K is a universal therapeutic target for human disease”, is 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 (Viagra, Cialis) to target GRP78 and related proteins, researchers prevented the replication of a variety of major viruses in infected cells, made antibiotic-resistant bacteria vulnerable to common antibiotics and found evidence that brain cancer stem cells were killed. Data were obtained in multiple brain cancer stem cell types, and using Influenza, Mumps, Measles, Rubella, RSV, CMV, Adenovirus, Coxsakie virus, 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 Paul Dent, Ph.D., professor in the department of biochemistry and molecular biology at VCU School of Medicine, and universal chair for signal transduction.
GRP78, a chaperone protein, helps shape chains of amino acids into proteins and then to keep those proteins active in the correct 3D shape. The OSU/Viagra drug combination attacks GRP78 and other chaperones, thereby killing cancer cells. After learning of the drug combination's effect on GRP78 in cancer cells, Dr. Dent and his team began to target GRP78 for infectious diseases such as viruses and bacteria.
The chaperone proteins are important in cancer cells or virus-infected cells because these cells make extra protein compared to normal/uninfected cells. The team found that the OSU/Viagra drug combination reduced infectivity via reduced viral receptor expression on the surface of target cells and the prevention of virus replication in infected cells. The drug combination was able to reduce expression of viral receptors for Ebola, Marburg, Hepatitis A, B and C, and Lassa fever viruses. In cancer cells the drug combination reduced the expression of oncogene receptors, too.
In bacteria, the drug combination reduced expression of the equivalent GRP78 protein, in Dna K bacteria, and induced cell death in pan-antibiotic resistant forms of E. coli, MRSE, MRSA, and N. gonorrhoeae.
“Thus, Dna K and bacterial phosphodiesterases are novel antibiotic targets, and inhibition of GRP78 is of therapeutic utility for cancer and also for bacterial and viral infections,” wrote the investigators.
“The findings open an avenue of being able to treat viral infections, infections that certainly most people would say we'll never be able to treat; they prove that GRP78 is a `drugable’ target to stop viruses from reproducing and spreading,” noted Dr. Dent. “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 in hospitals, we've got something that can help to treat the superbugs.”
According to Dr. Dent, the next steps have already been taken and are leading to new discoveries: “We know in mice that the OSU/Viagra treatment can kill 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 called `pumps’ in the mouse brain. Pumps are responsible for making tumor cells resistant to chemotherapy and for stopping life-saving brain cancer chemotherapy from entering into the brain and killing cancer.”