Treatment of actinic keratosis through inhibition of cyclooxygenase‐2: Potential mechanism of action of diclofenac sodium 3% in hyaluronic acid 2.5%

Abstract

Cyclooxygenase‐2 (COX‐2) and its metabolic product prostaglandin E2 (PGE2) are induced in response to growth factors, inflammatory cytokines, tumor promoters, activated oncogenes, and, in the skin, ultraviolet (UV) radiation. Accumulating evidence suggests a role for the COX‐2/PGE2 pathway in tumorigenesis in various tissue types including cutaneous squamous cell carcinoma. There is also strong evidence for a role in the development of actinic keratoses (AKs) — common dysplastic lesions of the skin associated with UV radiation overexposure — considered as part of a continuum with skin cancer. Non‐steroidal anti‐inflammatory drugs (NSAIDs) exert their anti‐inflammatory, analgesic, and antipyretic effects by reversibly or irreversibly acetylating COX isoforms, inhibiting downstream prostaglandins, and may have a chemopreventive role in malignancies, including skin cancer. Topical treatment of AK lesions with the NSAID diclofenac sodium 3% in combination with hyaluronic acid 2.5% has been shown to be effective and well tolerated, although the mechanism of action remains to be elucidated.

Regenerative Wound Dressings for Skin Cancer

“…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 ].…”

“…The current formulation contains 3% diclofenac in 2.5% hyaluronic acid which is applied twice daily for 8 weeks. Clearance rates range between 38% to 47% for actinic keratosis and 64.3% for superficial basal cell carcinoma [ 31 , 35 , 51 ]. Although it can be self-applied, there are frequent side effects associated, including erythema, erosion, allergic contact dermatitis, photoallergy, and pruritus [ 31 ].…”

Actinic keratosis: аctual view

“…Повышение уровня циклооксигеназы второго типа и простагландина Е2 в тканях ассоциировано с локальной иммуносупрессией, подавлением цитотоксической активности естественных киллеров, усиленной пролиферацией опухолевых клеток и неоангиогенезом. Ингибирование фермента циклооксигеназы второго типа, вероятно, может оказывать противоопухолевый эффект [12,17,32]. Гель, содержащий 3%-ный диклофенак натрия в 2,5%-ной гиалуроновой кислоте, рекомендован для терапии пациентов (особенно старше 75 лет) с множественными очагами актинического кератоза или имеющих «поле канцеризации» с количеством очагов более 3 на площади 25 см 2 [16].…”

“…В сравнении с 5-фторурацилом и имиквимодом препарат хорошо переносится пациентами, практически не вызывает воспалительных явлений, однако является менее эффективным [17]. В настоящее время в лечении актинического кератоза исследуется эффективность других нестероидных противовоспалительных средств, в частности пироксикама [5,32].…”

Diclofenac-Derived Hybrids for Treatment of Actinic Keratosis and Squamous Cell Carcinoma

“…Specifically, when surgical treatment is not feasible, topical pharmacotherapy can be a viable alternative. Diclofenac, a nonsteroidal anti-inflammatory drug, is the most commonly used topical agent to treat AK, due to its effectiveness, poor side effects, tolerability and low cost [2]. Topical diclofenac, effective use for NMSC, is also reported in recent clinical trials [3,4].…”