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Ginkgo Biloba Extract in the Treatment of Human Breast Cancer
Although our understanding of breast cancer has dramatically progressed, it still remains the major form of cancer among women. In the absence of the “magic bullet” drug for breast cancer therapy, many complementary and alternative therapies, including plant extracts, are under consideration. However, there is limited information about their mechanism of action. It is our hypothesis that the cytostatic effect of EGb 761 and its isolated bioactive component ginkgolide B (GKB) is mediated by specific Ginkgo-activated transcription factors that bind to Ginkgo-activated DNA response elements present in the promoter areas of EGb/GKB-responsive genes. It has previously shown that (i) PBR is over-expressed in highly invasive human breast cancer cell lines and biopsies as compared to non-invasive cell lines and control biopsies, (ii) the ability of highly aggressive breast cancer cells to form tumors in vivo may depend on the amount of PBR present in the cells and (iii) EGb 761 and GKB inhibit PBR expression and cell proliferation in aggressive human breast tumor cells both in vitro and in vivo. We propose to investigate the regulation of PBR gene transcription by EGb 761 and GKB in vitro and in vivo. This research will be undertaken with the following two independent but complementary specific aims: (i) identify and characterize the PBR gene promoter area that, in aggressive human breast cancer cells, mediates the response to EGb 761 and GKB treatment, leading to reduced cell growth, and (ii) examine the in vivo role of Ginkgo-activated response elements in suppressing PBR expression and cell growth in transgenic mice, in which PBR expression in the breast is induced in a tissue-specific manner.
We believe that the proposed experiments should demonstrate the mechanism of action by which if EGb 761 acts to prevent and/or stabilize the progression of cancer. Understanding the mechanism of action of Ginkgo biloba extracts would allow applying the knowledge of traditional medicine to modern medicine and, in the future, designing novel therapeutic entities for breast cancer.
Since the dawn of humanity, people have used plant products for the treatment of diseases. Traditional medicines have evolved in parallel with the development of human societies, and are as diversified as the populations who established them. Over the last century, the tremendous technical and scientific progress of the occidental society led to dramatic changes in our understanding of diseases and in the medical procedures used to treat them. As a result, scientists are putting enormous efforts in the development of synthetic compounds targeted at the cure of specific diseases. However, the failure of all “magic bullets” developed to prevent and/or cure these diseases brought the scientific community to look back at medicinal herbs as potential treatments. Ginkgo biloba is one of the most ancient trees and extracts from its leaves have been used in traditional medicine for several hundred years. Recent studies in the field of endocrinology indicated that the expression in the adrenal gland of a protein named the peripheral-type benzodiazepine receptor (PBR) could be regulated by the standardized extract of Ginkgo biloba leaves EGb 761, leading to reduced adrenal steroid production, and thus conrol the response of the body to stress. PBR is an intracellular protein that binds drugs, such as valium, and cholesterol. It was then shown that PBR expression is dramatically increased in aggressive human breast cancer cells where its expression correlates with the increased proliferation and the aggressive phenotype of the cells. Surprisingly, EGb 761 was shown to inhibit PBR expression and growth of aggressive human breast tumor cells in vitro, and in xenografts implanted in nude mice in vivo. Further genomic studies indicated that EGb 761 treatment regulates the expression of specific gene products, including oncogenes and growth factors, involved in pathways implicated in cell proliferation and tumorigenesis. Taken together, these data suggest that EGb 761 may exert cytostatic properties mediated, at least in part, by its ability to regulate gene expression. The molecular mechanism underlying the effects of EGB 761 on gene expression and cell proliferation will be investigated in the present application with the goal to demonstrate the mechanism of action by which EGb 761 acts to prevent and/or stabilize the progression of cancer. Understanding the mechanism of action of EGb 761 would allow applying the knowledge of traditional medicine to modern medicine and, in the future, designing novel therapeutic entities for breast cancer.