Pentamidine, an anti-protozoa drug, is described herein as a potent PTPase inhibitor with anti-cancer activity. Pentamidine at its therapeutic doses inhibits recombinant PRL phosphatases and inactivates intracellular PRLs in NIH3T3 transfectants. Pentamidine treatment at a nontoxic dose markedly inhibits the growth of WM9 human melanoma tumors in nude mice coincident with tumor cell necrosis and is capable of inactivating an ectopically expressed PRL-2 in the cancer cells. The drug has growth inhibitory activity against different human cancer cell lines that express the PRLs, and therefore has broad anti-cancer activity based on inactivating the oncogenic phosphatases.