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Research Articles: Therapeutics, Targets, and Development

PBISe, a novel selenium-containing drug for the treatment of malignant melanoma

Departments of ¹ Pharmacology, ² Pathology, and ³ Dermatology, ⁴ The Foreman Foundation for Melanoma Research, ⁵ Penn State Melanoma Therapeutics Program, and ⁶ Penn State Cancer Institute, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania

Requests for reprints: Gavin P. Robertson, Department of Pharmacology, The Pennsylvania State University College of Medicine, 500 University Drive, R130, Hershey, PA 17033. Phone: 717-531-8098; Fax: 717-531-5013. E-mail: gprobertson{at}psu.edu

Abstract

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. [Mol Cancer Ther 2008;7(5):1297–308]

Grant support: The American Cancer Society (RSG-04-053-01-GMC), NIH National Cancer Institute contract (NO2-CB-56603), the Foreman Foundation for Melanoma Research, Elsa U. Pardee Foundation, and Melanoma Research Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁷ Desai D, Madhunapantula SV, Gowdahalli K, El-Bayoumy K, Robertson GP, Amin S. Novel organoselenium analog of iNOS inhibitor for cancer therapy. Submitted for publication.

Received 11/13/07; revised 3/12/08; accepted 3/17/08.