Malignant melanoma is the most deadly form of
skin cancer due to its highly metastatic nature. Untargeted
therapies are ineffective for treating metastatic disease, leading to the development of agents specifically inhibiting
proteins or pathways deregulated in
melanoma. The deregulation of
inducible nitric oxide synthase (iNOS) is one such event occurring in
melanoma, and is correlated with poor survival. Current iNOS inhibitors, such as PBIT [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isothiourea], require high concentrations for clinical efficacy causing systemic toxicity. To develop more potent agents effective at significantly lower concentrations, a novel isosteric analogue of PBIT was synthesized, called PBISe [S,S'-1,4-phenylenebis(1,2-ethanediyl)bis-isoselenourea], in which
sulfur was replaced with
selenium. PBISe kills
melanoma cells >10-fold more effectively than PBIT, and cultured
cancer cells are 2- to 5-fold more sensitive than normal cells. Like PBIT, PBISe targets iNOS but also has new inhibitory properties acting as an Akt3 pathway inhibitor and
mitogen-activated protein kinase (MAPK) cascade activator, which causes decreased
cancer cell proliferation and increased apoptosis. Inhibition of cellular proliferation mediated by PBISe induced a G2-M phase cell cycle block linked to excessively high MAPK activity causing decreased
cyclin D1 and increased p21 as well as p27 levels. PBISe promotes apoptosis by inhibiting Akt3 signaling, elevating cleaved
caspase-3 and PARP levels. Compared with PBIT, PBISe reduced
tumor development by 30% to 50% in mice inducing a 2-fold increase in apoptosis with negligible associated systemic toxicity. Collectively, these results suggest that PBISe is a potent chemotherapeutic agent with novel properties enabling the targeting of iNOS, Akt3, and MAPK signaling, thereby promoting
melanoma cell apoptosis and inhibition of proliferation.