Imidazoquinoline Drugs Operate on the Opiate Growth Factor Pathway

Researchers have traced how the imidazoquinoline drugs imiquimod and resiquimod work to enhance the immune response to render it more effective in dealing with viral infections and cancerous conditions.

Imiquimod has been found to be highly effective for the treatment of external genital and anal warts, basal cell carcinoma, actinic keratoses, Kaposi's sarcoma, chronic hepatitis C infection, and intraepithelial carcinoma. It has been reported to be a toll-like receptor-7 agonist, and its anti-tumor effect exerted by modification of the immune response and stimulation of apoptosis.

To study the mode of action of imiquimod investigators at the Pennsylvania State University College of Medicine (Hershey, USA) employed 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. They reported in the August 2008, issue of the journal Experimental Biology and Medicine, which is currently available online, that the principle target of these drugs was the Opioid Growth Factor (OGF)-OGF receptor (OGFr) axis. This 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 eliminated the inhibitory effects of the drugs on cell replication.

Senior author Dr. Ian S. Zagon, professor of neural and behavioral sciences at Pennsylvania State University College of Medicine, said, "Our data brings a paradigm shift to our thinking about a drug widely used in the clinics. Rather than imiquimod activity being mediated by induction of various cytokines, including interferon, tumor necrosis factor-alpha, interleukin-1- alpha, and interleukin-12 as currently thought, an entirely new pathway - native to body chemistry - has been discovered to regulate cell proliferation by imidazoquinolines.”


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Pennsylvania State University College of Medicine