BACKGROUND: Amplification of the proto-oncogene c-myc has been identified as one of the most common genetic alterations in prostate cancer, thus making it an attractive therapeutic target. However, certain prostate cancer cells are unresponsive to c-Myc inhibition. The purpose of this study was to test the hypothesis that effective growth inhibition in the refractory cancer cells can be achieved by blocking c-myc along with a growth factor using a novel phosphorodiamidate morpholino antisense oligomer-based approach. Human chorionic gonadotropin, a growth factor implicated in neoplasm, causes activation of c-myc through a G-protein-coupled pathway of signal transduction. METHODS: In this study, the effect of inhibition of beta-hCG and c-myc singly or in combination was evaluated in DU145 (RB -/-, p53-/-, androgen-independent) and LNCaP (Rb+/+, p53 +/+, androgen-sensitive) human prostate cancer cell lines and in a DU145 subcutaneous xenograft murine model. RESULTS: Antisense phosphorodiamidate morpholino oligomers directed against beta-hCG and c-myc caused a specific decrease of the target protein levels. Unlike LNCaP cells, DU145 cell growth was refractory to c-Myc inhibition. Unresponsiveness to c-myc inhibition in DU145 cells was overcome by targeting both beta-hCG and c-myc genes, resulting in potentiation of the antiproliferative effect seen with inhibition of beta-hCG alone. CONCLUSIONS: The inhibition of beta-hCG sensitizes prostate cancer cells to the antiproliferative effects of c-Myc inhibition, including tumors that are refractory to c-Myc decrease alone.