The 2,6,9-trisubstituted
purine group of
cyclin dependent kinase inhibitors have the potential to be clinically relevant inhibitors of
cancer cell proliferation. We have recently designed and synthesized a novel dansylated analog of
purvalanol B, termed
VMY-1-103, that inhibited cell cycle progression in
breast cancer cell lines more effectively than did
purvalanol B and allowed for uptake analyses by fluorescence microscopy. ErbB-2 plays an important role in the regulation of signal transduction cascades in a number of epithelial
tumors, including
prostate cancer (PCa). Our previous studies demonstrated that transgenic expression of activated ErbB-2 in the mouse prostate initiated PCa and either the overexpression of ErbB-2 or the addition of the ErbB-2/ErbB-3
ligand,
heregulin (
HRG), induced cell cycle progression in the
androgen-responsive
prostate cancer cell line, LNCaP. In the present study, we tested the efficacy of
VMY-1-103 in inhibiting
HRG-induced cell proliferation in LNCaP
prostate cancer cells. At concentrations as low as 1 μM,
VMY-1-103 increased both the proportion of cells in G(1) and p21(CIP1)
protein levels. At higher concentrations (5 μM or 10 μM),
VMY-1-103 induced apoptosis via decreased mitochondrial membrane polarity and induction of p53 phosphorylation,
caspase-3 activity and PARP cleavage. Treatment with 10 μM
Purvalanol B failed to either influence proliferation or induce apoptosis. Our results demonstrate that
VMY-1-103 was more effective in inducing apoptosis in PCa cells than its parent compound,
purvalanol B, and support the testing of
VMY-1-103 as a potential small molecule inhibitor of
prostate cancer in vivo.