Imiquimod

Hurwitz, Daniel; Pincus, Laura; Kupper, Thomas S.

doi:10.1001/archderm.139.10.1347

Cited by 51 publications

(3 citation statements)

References 44 publications

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“…This has been confirmed at the tissue level, as histologic analysis of imiquimod treated non-melanoma skin cancers develop lymphocyte-rich (CD4, CD8-T-lymphocytes and NK-cells) infiltrates which are thought to be anti-tumor effector cells (44). Second, imiquimod induces a strong local inflammatory response in treated cancerous tissue (45), and cytokine production (such as TNF-α) which may be cytotoxic to tumor cells. Third, imiquimod has been demonstrated to promote the development of cytotoxic “killer” dendritic cells, which may also attack tumors (46).…”

Section: Discussionmentioning

confidence: 99%

Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells

Fishelevich

Zhao

Tuchinda

et al. 2011

The Journal of Immunology

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Imiquimod is a TLR7/8 agonist that has anti-cancer therapeutic efficacy in the treatment of pre-cancerous skin lesions and certain non-melanoma skin cancers. To test our hypothesis that imiquimod enhances DNA repair as a mechanism for its anticancer activity, the nucleotide excision repair genes were studied in bone marrow derived cells. Imiquimod enhanced the expression of XPA and other DNA repair genes (qPCR analysis), and resulted in an increased nuclear localization of the DNA repair enzyme XPA. This was dependent on MyD88, as bone marrow derived cells from MyD88−/− mice did not increase XPA gene expression, and did not enhance the survival of MyD88−/− derived bone marrow derived cells after UVB exposure as was observed in bone marrow derived cells from MyD88+/+ mice. Imiquimod also enhanced DNA repair of UVL irradiated gene expression constructs, and accelerated the resolution of cyclobutane pyrimidine dimers (CBPD) after UVL exposures in P388 and XS52. Lastly, topical treatment of mouse skin with 5% imiquimod cream prior to UVL irradiation resulted in a decrease in the number of cyclobutane pyridimine dimer positive, APC that were found in local lymph nodes 24 hours after UVL irradiation in both wild type and IL-12 gene targeted mice. In total, these data support the idea that TLR7 agonists such as imiquimod enhance DNA repair in bone marrow derived cells. This property is likely to be an important mechanism for its anti-cancer effects, because it protects cutaneous APC from the deleterious effects of UVL.

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Section: Discussionmentioning

confidence: 99%

Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells

Fishelevich

Zhao

Tuchinda

et al. 2011

The Journal of Immunology

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“…Topical imiquimod is a ligand of the Toll‐like receptors 7 and 8 on dendritic cells, increasing innate and adaptive immune responses and showing antiviral and antitumor activity 3,4 …”

Section: Discussionmentioning

confidence: 99%

Treatment of Classic Kaposi's Sarcoma with Topical Imiquimod

Goiriz

Ríos‐Buceta

Arriba

et al. 2009

Dermatologic Surgery

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“…Overall, although some aspects of the TLR-dependent activity of imiquimod and related compounds remain to be determined, there is compelling evidence for the notion that imiquimod -via stimulation of antitumoral T cells through activation of antigen presenting cells -exerts its activity primarily at the interface between innate and acquired immunity [82,83].…”

Section: Cellular Immune Reactions Induced By Imidazoquinolinesmentioning

confidence: 99%

The Antitumoral Mode of Action of Imiquimod and Other Imidazoquinolines

Schön

2007

CMC

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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.

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Imiquimod

Cited by 51 publications

References 44 publications

Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells

Imiquimod-Induced TLR7 Signaling Enhances Repair of DNA Damage Induced by Ultraviolet Light in Bone Marrow-Derived Cells

Treatment of Classic Kaposi's Sarcoma with Topical Imiquimod

The Antitumoral Mode of Action of Imiquimod and Other Imidazoquinolines

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