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ORIGINAL RESEARCH ARTICLE

Imiquimod Upregulates the Opioid Growth Factor Receptor to Inhibit Cell Proliferation Independent of Immune Function

Ian S. Zagon^*,1, Renee N. Donahue^*, Moshe Rogosnitzky and Patricia J. Mclaughlin^*

^* Department of Neural and Behavioral Sciences, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033; and MedInsight, Telz Stone, Israel

To whom requests for reprints should be addressed at ¹ Department of Neural and Behavioral Sciences, H109, The M.S. Hershey Medical Center, 500 University Drive, Rm. C3729, Hershey, PA 17033. E-mail: isz1{at}psu.edu

The imidazoquinoline compounds imiquimod and resiquimod are low-molecular-weight immune response modifiers that have potent anti-viral and anti-tumor properties. The mechanism by which they exert their effects remains unclear. Using pancreatic and colorectal cancer cells, as well as squamous carcinoma cells of the head and neck in tissue culture, which eliminated the immune system and toll-like receptors, we show that the imidazoquinolines upregulate the Opioid Growth Factor receptor (OGFr), which in turn stimulates the interaction of the OGF-OGFr axis. This native, tonically active inhibitory pathway regulates cell proliferation by modulating cyclin dependent kinase inhibitors, resulting in a retardation of cells at the G₁-S interface of the cell cycle. Neutralization of OGF or knockdown of OGFr by siRNA technology eliminates the inhibitory effects of imidazoquinolines on cell replication. This exciting new knowledge of the mechanism of imidazoquinolines has important physiological relevance, and allows strategies to be developed for the use of these agents that will enhance effectiveness as well as attenuate side-effects.

Key Words: cell proliferation • imiquimod • opioid growth factor • cancer • immunity