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Psoralidin, an Herbal Molecule, Inhibits Phosphatidylinositol 3-Kinase–Mediated Akt Signaling in Androgen-Independent Prostate Cancer Cells

Authors' Affiliations: ¹ Department of Clinical Laboratory Sciences, College of Health Sciences; ² Department of Pharmaceutical Sciences, College of Pharmacy; and ³ Departments of Surgery/Urology and Molecular & Cellular Biochemistry and the Markey Cancer Center, University of Kentucky, Lexington, Kentucky

Requests for reprints: Chendil Damodaran, Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Room 124E, 900 South Limestone Street, Lexington, KY 40536-0200. Phone: 859-323-1100, ext. 80851/80879; Fax: 859-323-8957; E-mail: dchen2{at}uky.edu.

The protein kinase Akt plays an important role in cell proliferation and survival in many cancers, including prostate cancer. Due to its kinase activity, it serves as a molecular conduit for inhibiting apoptosis and promoting angiogenesis in most cell types. In most of the prostate tumors, Akt signaling is constitutively activated due to the deletion or mutation of the tumor suppressor PTEN, which negatively regulates phosphatidylinositol 3-kinase through lipid phosphatase activity. Recently, we identified a natural compound, psoralidin, which inhibits Akt phosphorylation, and its consequent activation in androgen-independent prostate cancer (AIPC) cells. Furthermore, ectopic expression of Akt renders AIPC cells resistant to chemotherapy; however, psoralidin overcomes Akt-mediated resistance and induces apoptosis in AIPC cells. While dissecting the molecular events, both upstream and downstream of Akt, we found that psoralidin inhibits phosphatidylinositol 3-kinase activation and transcriptionally represses the activation of nuclear factor-B and its target genes (Bcl-2, Survivin, and Bcl-xL, etc.), which results in the inhibition of cell viability and induction of apoptosis in PC-3 and DU-145 cells. Interestingly, psoralidin selectively targets cancer cells without causing any toxicity to normal prostate epithelial cells. In vivo xenograft assays substantiate these in vitro findings and show that psoralidin inhibits prostate tumor growth in nude mice. Our findings are of therapeutic significance in the management of prostate cancer patients with advanced or metastatic disease, as they provide new directions for the development of a phytochemical-based platform for prevention and treatment strategies for AIPC.

Key Words: Akt signaling • apoptosis • natural compound