Methylseleninic acid enhances the effect of etoposide to inhibit prostate cancer growth in vivo

✍ Scribed by Oscar Gonzalez-Moreno; Victor Segura; Diego Serrano; Paul Nguewa; Javier de las Rivas; Alfonso Calvo

• Publisher: John Wiley and Sons
• Year: 2007
• Tongue: French
• Weight: 363 KB
• Volume: 121
• Category: Article
• ISSN: 0020-7136
• DOI: 10.1002/ijc.22764

✦ Synopsis

Abstract

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. © 2007 Wiley‐Liss, Inc.