Imiquimod: mode of action.
OBJECTIVE
Since imiquimod, a nucleoside analogue of the imidazoquinoline family, has shown efficacy against many tumour entities, its mode of action has become a focus of scientific interest.


RESULTS
The major biologic effects of imiquimod are mediated through agonistic activity towards toll-like receptors (TLR) 7 and 8, and consecutively, activation of nuclear factor-kappa B (NF-kappaB). The result of this activity is the induction of pro-inflammatory cytokines, chemokines and other mediators leading to activation of antigen-presenting cells and other components of innate immunity and, eventually, the mounting of a profound T-helper (Th1)-weighted antitumoral cellular immune response. Several secondary effects on the molecular and cellular level may also be explained, at least in part, by the activation of NF-kappaB. Moreover, independent of TLR-7 and TLR-8, imiquimod appears to interfere with adenosine receptor signalling pathways, and the compound causes receptor-independent reduction of adenylyl cyclase activity. This novel mechanism may augment the pro-inflammatory activity of the compound through suppression of a negative regulatory feedback mechanism which normally limits inflammatory responses. Finally, imiquimod induces apoptosis of tumour cells at higher concentrations. The pro-apoptotic activity of imiquimod involves caspase activation and appears to depend on B cell lymphoma/leukemia protein (Bcl)-2 proteins.


CONCLUSIONS
Overall, imiquimod acts on several levels, which appear to synergistically underlie the profound antitumoral activity of the compound.
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Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany. michael.schoen@virchow.uni-wuerzburg.de
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D000634:Aminoquinolines / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects; D006801:Humans; D000077271:Imiquimod; D007111:Immunity, Cellular / Q000187:drug effects; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology; D018047:Receptors, Purinergic P1 / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000819:agonists
D000634:Aminoquinolines; D000970:Antineoplastic Agents; D018047:Receptors, Purinergic P1; D051193:Toll-Like Receptors; D000077271:Imiquimod