M P Schön1, M Schön. 1. Rudolf Virchow Center, DFG Research Center for Experimental Biomedicine and Department of Dermatology, Julius-Maximilians-University, Würzburg, Germany. michael.schoen@virchow.uni-wuerzburg.de
Abstract
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.
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.
Authors: Jessica M Donigan; Mark A Hyde; David E Goldgar; Michael L Hadley; Marianne Bowling; Glen M Bowen Journal: JAMA Dermatol Date: 2018-08-01 Impact factor: 10.282
Authors: Anna J X Zhang; Can Li; Kelvin K W To; Hou-Shun Zhu; Andrew C Y Lee; Chuan-Gen Li; Jasper F W Chan; Ivan F N Hung; Kwok-Yung Yuen Journal: Clin Vaccine Immunol Date: 2014-02-12