Suppression of tumor recurrence and metastasis by a combination of the PHSCN sequence and the antiangiogenic compound tetrathiomolybdate in prostate carcinoma

The invasion of human DU145 prostate cancer cells, mediated by plasma fibronectin, was effectively inhibited in a rat tumor model through treatment with the Ac-PHSCN-NH(2) peptide. The PHSRN sequence of plasma fibronectin stimulated DU145 cell invasion, but the PHSCN peptide served as a competitive inhibitor, blocking PHSRN-mediated invasion. In this study, we investigated whether PHSCN could prevent the recurrence and metastasis of DU145 tumors following excision of the primary tumor in an athymic nude mouse model. Mice treated intravenously with Ac-PHSCN-NH(2) peptide three times weekly remained tumor-free for over 30 weeks after primary tumor excision, while untreated mice succumbed to recurrence and/or metastatic disease much earlier. Given the essential role of angiogenesis in solid tumor growth, we also assessed the effectiveness of copper depletion induced by tetrathiomolybdate (TM) in slowing tumor growth in the Dunning prostate cancer model. Copper-deficient mice exhibited a significant reduction in primary tumor size. To further reduce tumor growth at both primary and metastatic sites, we combined the anti-invasion Ac-PHSCN-NH(2) peptide with TM. This combination therapy resulted in improved survival, fewer metastatic lesions,Ac-PHSCN-NH2 and excellent tolerability.