New therapeutic agents are needed for the treatment of
androgen-independent
prostate cancer (PrCa). We have investigated the effect of
methylseleninic acid (MSA) on
tumor stage-specific prostate cells derived from the C3 (1)/Tag model for PrCa: Pr111, a slow-growing and nontumorigenic cell line isolated from a prostate intraepithelial
neoplasia lesion;
Pr14, a tumorigenic line derived from a primary
tumor; and Pr14C1, a sub-clone of
Pr14 explanted from a lung
metastasis. We demonstrate that MSA strongly inhibits cell growth and induces apoptosis in C3 (1)/Tag
tumor cells, in a dose-dependent manner. A decrease in phosphorylated ERK1/2 and AKT was also found in
tumor cells, but not in Pr111. Microarray analysis using affymetrix showed that the number of genes with an altered expression in
tumor cells is significantly higher (p < 0.01) than in nontumoral cells. Pathways analyses revealed a decrease in the expression of genes involved in metabolism (Fabp5, Cyba), signal transduction (ERK, AKT), angiogenesis (neuropilin-1, Flt-4) and transcription (
cAMP response element-binding protein) in
tumor cells. The expression of
neuropilin-1, a
protein involved in
VEGF signaling and
tumor angiogenesis, was 97-fold repressed in
Pr14 cells treated with MSA. Combination treatments using low doses of
etoposide or
taxotere (
docetaxel), plus low doses of MSA revealed a strong enhancement of cell growth inhibition and apoptosis in
tumor cells. Our in vivo studies using
Pr14 cells xenografted into nude mice demonstrated that MSA significantly enhances the chemotherapeutical effect of
etoposide, resulting in 78.3%
tumor growth inhibition. These results suggest that MSA could be used against PrCa to enhance the effect of
etoposide.