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-kappaB 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.