Targeting Prostate Cancer Cells with Bioflavonoids
Division of Cancer BiologyCurrent treatments for prostate cancer – including surgery, radiation therapy, and hormone therapy – can be effective, and in some cases cure men of their cancer. However, all of these treatments can cause major side effects. Researchers are looking for additional targeted therapies for prostate cancer that will halt the growth of cancer cells while leaving normal cells largely unaffected.
The type II [3H]estradiol binding site plays an important role in regulating cell proliferation in prostate and other cancers. In normal cells, a molecule called methyl p-hydroxyphenyllactate (MeHPLA) is thought to occupy most of the type II [3H]estradiol binding sites, blocking cell-signaling pathways that encourage the cells to divide. Malignant cells, including breast and prostate cancer cells contain higher than normal levels of a type of molecule called esterase that destroys MeHPLA, thereby freeing the type II [3H] estradiol binding sites and triggering DNA synthesis and cancer cell proliferation. Thus, drugs that act like MeHPLA, but are not destroyed by this esterase, are potentially very effective anticancer agents.
Barry Markaverich, Ph.D., associate professor in the Department of Molecular and Cellular Biology at Baylor College of Medicine in Houston, Texas has been studying the type II [3H]estradiol binding sites for over 30 years. Dr. Markaverich and his colleagues discovered that MeHPLA is a metabolite of bioflavonoids – compounds commonly found in plants and thought to have potential medicinal properties, including anti-cancer effects. Bioflavonoids can be obtained in the diet by the consumption of fruits and vegetables.
His laboratory has extended this understanding to a search for natural and synthetic compounds to replace the destroyed MeHPLA in cancer cells, and thus block uncontrolled cell division. Luteolin – a bioflavonoid found in some vegetables, herbs, and other plant products consumed in the diet – is structurally similar to MeHPLA and can successfully bind to the type II [3H]estradiol binding sites.
In a recent set of experiments*, Dr. Markaverich and his colleagues used prostate cancer cell lines to better understand the effects on gene regulation of luteolin and two structurally similar synthetic compounds they designed: BMHPC and ZN-2. The researchers found that luteolin treatment significantly altered 32 important cell regulatory pathways involved in the cell cycle and RNA transcription, which may affect cancer cell growth.
With NCI funding**, Dr. Markaverich is currently examining how luteolin, BMHPC, and ZN-2 affect the epidermal growth factor signaling pathway – a cell-signaling pathway often disregulated in cancer cells. The researchers will focus particularly on an oncogene called c-fos and are planning to test the three compounds in mouse models of prostate cancer.
Since type II [3H]estradiol binding sites are found in all cells, Dr. Markaverich proposes that their compounds could be effective against hormonedependent prostate cancers (that require the presence of hormones to grow) as well as hormone-independent versions. These types of compounds previously showed anti-tumor activity in all of the cell lines in the Human Tumor Cell Line Screen belonging to NCI’s Developmental Therapeutics Program.
NCI Program Director Neeraja Sathyamoorthy Ph.D., commented, “Dr. Markaverich’s group is delineating the mechanism by which dietary agents with structures resembling estrogen, inhibit the proliferation of prostate cancer cells. Their group has demonstrated that luteolin regulates gene expression by epigenetic mechanisms. Elucidating the mechanism of action of these agents could lead to the development of type II site binding compounds that inhibit the growth of prostate cancer cells. This could help identify potential strategic sites for targeted therapy.”
* Shoulars K, Rodriguez MA, Thompson T, Markaverich BM. Regulation of cell cycle and RNA transcription genes identified by microarray analysis of PC-3 human prostate cancer cells treated with luteolin. Journal of Steroid Biochemistry and Molecular Biology, January 2010;118(1-2):41-50.
**Grant Number: 5R01CA128932-02