The Antitumoral Mode of Action of Imiquimod and Other Imidazoquinolines

Abstract

Imiquimod, the lead compound of the imidazoquinoline family of nucleoside analogues, has shown good efficacy against a variety of tumors of different origin. The mode of action of imiquimod and related compounds, which we have begun to understand in some detail in recent years, is complex and interesting inasmuch as it appears to comprise several presumably mutually enhancing components. Predominant amongst its actions is the induction of pro-inflammatory cytokines through agonistic activity towards Toll-like receptor (TLR)-7 and TLR-8, and consecutively, activation of the central transcription factor NF-kappaB. This activity stimulates the production of pro-inflammatory cytokines, chemokines and other mediators resulting in activation of antigen-presenting cells and the mounting of a profound Th1-weighted antitumoral cellular immune response. In addition, there are a number of secondary effects on the molecular and cellular level that can be explained through the activation of NF-kappaB. The pro-inflammatory activity of imiquimod appears to be augmented by suppression of a negative regulatory feedback mechanism which normally limits inflammatory responses. This is achieved independent of TLR-7 and TLR-8 through interference with adenosine receptor signaling pathways, particularly the A(2A) subtype, and receptor-independent reduction of adenylyl cyclase activity. Finally, at higher, albeit therapeutically relevant concentrations, imiquimod exerts a pro-apoptotic activity against tumor cells. Induction of apoptosis by imiquimod appears to be dependent on Bcl-2 proteins and involves caspase activation. The combination of multiple, presumably synergistic anti-tumoral functions by a single compound represents an interesting principle of pathogenesis-oriented, anti-neoplastic therapy.

TLR7 and TLR8 as targets in cancer therapy

“…It is the lead compound of the imidazoquinoline family and has been studied most extensively. Most of the findings concerning the antitumoral mode of action of TLR7/8 agonists, clinical efficacy and safety reviewed here have been obtained with imiquimod (Scho¨n and Scho¨n, 2007). Imiquimod activates preferentially TLR7; its agonistic activity at TLR8 appears to be much weaker (Lee et al, 2003).…”

Identification of Novel Formyl Peptide Receptor-Like 1 Agonists That Induce Macrophage Tumor Necrosis Factor α Production

“…natural and synthetic agents with antimicrobial and antitumor properties, such as imidazoquinolines and taxanes, have been shown to induce a broad range of cytokines in cell culture and/or in vivo (Burkhart et al, 1994;Schön and Schön, 2007). Furthermore, induction of TNF-␣ by imidazoquinolines has been shown to be mediated through agonist activity toward Toll-like receptor (TLR)-7 and TLR-8 (Schön and Schön, 2007).…”

Association between Toll-like receptor 7 Gln11Leu single-nucleotide polymorphism and basal cell carcinoma

“…They induce the activation of nuclear factor-κB, which leads to the transcription of cytokines and chemokines through a myeloid differentiation protein 88-dependent pathway. Topical imiquimod was the first Food and Drug Administration approved drug acting as an agonist of TLR7 (40,41). Several studies reported high efficacy of imiqimod for the treatment of superficial BCC with a cure rate ranging from 43-94% (42-45), whereas it is less efficacious for nodular BCC with a cure rates of 50-65% (43,46).…”