Mediators of Inflammation in Topical Therapy of Skin Cancers

Abstract

Taking into consideration that the immune system plays a very important role in the development of melanoma and non-melanoma skin cancers, which have a high prevalence in immunosuppressed patients and after prolonged ultraviolet radiation, the interest in developing novel therapies, in particular targeting the inflammation in cancer, has increased in the past years. The latest data suggest that therapies such as imiquimod (IMQ), ingenol mebutate (IM), 5-fluorouracil (5-FU), retinoids, and nonsteroidal anti-inflammatory drugs (NSAIDs) have been used with success in the topical treatment of some cancers. Herein, we review the topical treatment targeting the inflammation in skin cancer and the mechanisms involved in these processes. Currently, various associations have shown a superior success rate than monotherapy, such as systemic acitretin and topical IMQ, topical 5-FU with tretinoin cream, or IMQ with checkpoint inhibitor cytotoxic T lymphocyte antigen 4. Novel therapies targeting Toll-like receptor-7 (TLR-7) with higher selectivity than IMQ are also of great interest.

Regenerative Wound Dressings for Skin Cancer

“…Imiquimod for topical administration is used as 3.75% or 5% creams and treatment involves 5 to 7 times per week applications, once a day, for 6 to 12 weeks [ 31 ]. In this manner, it provides a non-surgical, non-invasive, self-administered therapeutic option with relatively low costs [ 35 , 38 ]. For 6-week treatments using 5% creams, clearance rates are between 52% and 81% [ 31 , 32 ].…”

“…5-Fluorouracil (5-fluoro-1 H -pyrimidine-2,4-dione, Figure 1 ), is a pyrimidine analogue [ 31 , 39 , 40 , 41 ] which belongs to the class of anti-metabolite drugs [ 31 , 35 , 41 , 42 , 43 ]. As a chemotherapeutic agent, it has been widely applied in the treatment of malignant diseases [ 42 ].…”

“…There is a dual underlying mechanism that could be attributed to its anti-cancer potential, consisting of mitochondrial destruction induced by increased intracellular calcium levels and subsequent epidermal cell death through necrosis and apoptosis. The following stage involves protein kinase C activation, which further stimulates infiltration of neutrophils, production of pro-inflammatory cytokines, expression of endothelial adhesion molecules, and formation of tumor-specific antibody, leading to a neutrophil-mediated antibody-dependent cellular cytotoxicity [ 31 , 35 , 45 , 46 , 47 ]. In this manner, inflammation manifests within hours of application through erythema and edema and subsequent pustules, epidermal flaking, and crusting, which subside in less than 2 weeks [ 47 ].…”

“…Diclofenac (2-(2-(2,6-dichlorophenylamino)phenyl)acetic acid, Figure 1 ), also known for its sodium salt sold as Voltaren, is a non-steroidal anti-inflammatory drug widely used for actinic keratosis treatment and can be an adjuvant for basal cell carcinoma, squamous cell carcinoma, and melanoma skin metastases therapy [ 35 , 49 , 50 ].…”

“…Its mechanism of action, although not completely elucidated, could involve the inhibition of cyclooxygenase-1 and -2, enzymes involved in reducing prostaglandin formation from arachidonic acid, which reduces PGE2 synthesis and dysplastic keratinocytes in cancerous lesions [ 31 , 35 , 50 , 51 ]. Additionally, it might interfere with the SHH and Wnt signaling and lead to cancer cell apoptosis and inhibit angiogenesis and proliferation [ 31 , 35 , 50 ].…”