Abstract
Prostate cancer is the most common malignancy among men in Western societies, and current therapeutic approaches are evolving to manage growth, recurrence, and mortality neoplasia. Membrane androgen receptors (mARs) have been characterized in human prostate cancer, being preferentially expressed in tumor rather than benign gland areas. Furthermore, mAR agonists (protein-conjugated testosterone) decrease in vitro prostate cancer cell growth and induce apoptosis, whereas in vivo they regress growth of tumor xenografts alone or in combination with taxane drugs. In this respect, targeting mARs might be a novel therapeutic approach in prostate cancer. In our search for new small-molecule ligands of mAR, we report that flavanol dimers B1-B4 (oligomeric procyanidins) decrease in vitro growth of the androgen-sensitive (LnCaP) and androgen-resistant (DU145) human prostate cancer cell lines in the following order: B3 = B4 > B2 ≫ B1 (LnCaP) and B2 ≫ B3 = B4 ≫ B1 (DU145). Some of these analogs were previously shown to trigger signaling cascades similar to testosterone-bovine serum albumin (BSA) conjugate. Galloylation does not confer an additional advantage; however, oleylation increases the dimers' antiproliferative potency by a factor of 100. In addition, we report that B2, oleylated or not, displaces testosterone from mARs with an IC50 value at the nanomolar range and induces DU145 tumor xenograft regression by 50% (testosterone-BSA 40%). In this respect, oleylated B2 is a potent small-molecule agonist of mAR and could be a novel therapeutic agent for advanced prostate cancer, especially when taking into account the absence of androgenic actions and (liver) toxicity.
Footnotes
This work was partially supported by the Greek Ministry of Health [Grant 128937/2008] and the Research Account of the University of Crete.
Conflict of interest: M.K., K.T., F.M., V.P., A.-P.N., J.V., and E.C. are inventors in patent applications related to the subject.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.177246.
↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
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ABBREVIATIONS:
- OPC
- oligomeric proanthocyanidin
- BSA
- bovine serum albumin
- PBS
- phosphate-buffered saline
- HPLC
- high-performance liquid chromatography
- FAK
- focal adhesion kinase
- PI3K
- phosphatidylinositol 3-kinase
- ER
- estrogen receptor.
- Received November 11, 2010.
- Accepted January 3, 2011.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics
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