UM Nobel Laureate Researcher Discovers Antioxidant Activity Of Growth Hormone-Releasing Hormone Antagonists

Main Category: Cancer / Oncology
Article Date: 29 Dec 2008 - 2:00 PDT

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Researchers at the University of Miami Miller School of Medicine have discovered the antioxidant activity of growth hormone-releasing hormone (GHRH) antagonists in cancers. This discovery could lead to novel therapies against various cancers as well as neurodegenerative diseases, such as Alzheimer's. The results of the study, by Nobel laureate Andrew V. Schally, Ph.D., M.D.h.c., D.Sc.h.c., distinguished medical research scientist in the Department of Veterans Affairs, and distinguished professor of pathology at the Miller School and, and Nektarios Barabutis, M.Sc., Ph.D., research associate professor of pathology at the Miller School and Miami VA Medical Center, are published in the December 8 edition of the Proceedings of the National Academy of Sciences.

Dr. Schally, who is also professor of medicine in the Division of Hematology-Oncology at the Sylvester Comprehensive Cancer Center, has been a world leader in the study of hormone-related cancers. Last year, he and his colleagues showed that a splice variant (SV1) of a hormone receptor stimulated breast cancer cells in the laboratory. SV1 is a hormone growth factor receptor which responds to growth hormone-releasing hormone (GHRH). GHRH normally binds to receptors in the pituitary gland, stimulating the release of growth hormone, which induces normal tissue growth.

However, GHRH also acts as a growth factor in various tumors. Dr. Schally and Dr. Barabutis previously demonstrated that GHRH is a growth factor for prostate, lung, breast and other cancers. GHRH antagonists, which Dr. Schally has been developing for 15 years, block the action of GHRH, and thereby strongly inhibit the growth of cancer.

"The influence of GHRH antagonists on oxidative stress" says Dr. Schally, "has not been investigated before and it is critical that we learn their effect on the development and progression of cancer." In this study, he worked with Dr. Barabutis to test the antioxidant activity of GHRH antagonists on the LNCaP human prostate cancer cell line.

Oxidants, which are harmful, are generated from our own bodies and some external sources through our lives. As we get older, oxidants build up because the body's defense system isn't able to protect as well. Oxidative stress, or the accumulation of oxidants in the body, contributes to the process of aging and the development of cancer.

Dr. Schally and Dr. Barabutis tested antagonistic analogues of GHRH, synthesized by Dr. Schally's team, Martha Zarandi, Ph.D., D.Sc., visiting assistant professor of pathology, Jozsef L. Varga, Ph.D., research associate professor of medicine, and Ren-Zhi Cai, Ph.D., visiting associate professor of pathology. Dr. Schally and Dr. Barabutis discovered that GHRH antagonists inhibited the growth of LNCaP prostate cancer cells by reducing the amount of free radicals in the cells. This is the first demonstration that GHRH antagonists possess antioxidant activity. "This discovery further elucidates the mechanism of action of these compounds that we are developing into a new therapy for cancer" says Dr. Schally, who is a world leader in targeting hormone-related cancers.

Besides providing novel approaches to cancer treatment, this discovery could have other potential therapeutic applications. Increased oxidative stress is involved in the pathogenesis of diabetes and its major complications including retinopathy, neuropathy and nephropathy as well as in development of neurodegenerative diseases such as Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and Huntington's disease. "We think these compounds could be used not only as anti-cancer drugs but also to treat other diseases related to increased oxidative stress" says Dr. Schally.

Next, Dr. Schally and Dr. Barabutis plan to conduct various tests in-vivo on brain tissue of rats and human neural cell lines, to determine if GHRH antagonists have the same antioxidative effects on neural tissues. They will also examine the effects of GHRH antagonists on neuronal cultures in an endeavor to develop a new therapy for neurodegenerative diseases. This project is already leading to extensive national/international collaboration.

Lisa Worley
Office of Communications
University of Miami Miller School of Medicine
http://www.med.miami.edu