Druggable Targets for Melanoma: Skin Aquaporins

AQP-modulating agent discovery has proved challenging, but many powerful AQP3 permeating molecules have been identified.

The human body’s largest organ—the skin—serves as a first line of defense, and has essential immunological and biochemical roles. Aquaporins (AQPs), a group of membrane channels responsible for transmission of water and other small uncharged solutes, are heavily involved in the skin’s physiology. They are vital for skin hydration and wound healing. AQP dysfunction has been linked to melanoma and other skin disorders.

A review published in Biochimie in May 2021 suggests AQPs as potential drug targets for skin cancer. Recent innovations in melanoma biology indicate expression of 8 of the 13 AQP isoforms in melanoma cells. This review discusses current knowledge of AQP envelopment in skin’s function and pathology. Many studies outlined focus on AQP1 and AQP3 as possible melanoma drug targets.

In a small study comprised of 78 melanoma patients, AQP1-expressing cutaneous melanoma cells were present in 52 subjects. Those at high risk had elevated AQP1 levels. Follow-up with these patients showed a reduced survival rate, correlating AQP1 over-expression with negative prognosis. These authors found the same inverse relationship with AQP1 expression and survival in patients with extracranial metastasis. This data suggests AQP1 is a likely prognostic indicator for human cutaneous melanoma.

Another study that focused on AQP1’s anti-angiogenic features showed melanoma-afflicted mice with 75% tumor volume reduction after 6 days when injected intratumorally with AQP1 siRNA. Subsequent injections revealed inhibition of tumor growth. The same authors treated a mouse’s melanoma with these injections for 10 days and results showed inhibition of lung nodule growth and twice the survival rate compared to control mice.

AQP-modulating agent discovery has proved challenging, but many powerful AQP3 permeating molecules have been identified. Auphen, a gold-based compound, showed AQP3 permeability inhibition, reducing spread by 50% in AQP3-expressing tumors.

Cuphen, a strong copper-based AQP3 inhibitor, tended to suppress cell growth with minimal toxicity when studied in mice with melanoma. These results indicate auphen and cuphen as possible treatments for melanoma and other solid tumors.

Present knowledge suggests AQPs as promising drug targets for melanoma and other skin ailments. Further research regarding the roles of AQPs in both the presence and absence of skin disease is crucial to understand how AQP modulators can be applied in clinical practice.

Sara L. Tolliday, PharmD, RPh,is a full-time pharmacist at Wentworth-Douglass Hospital, Outpatient Pharmacy, Dover, NH.

REFERENCE

da Silva IV, Silva AG, Pimpão C, Soveral G. Skin aquaporins as druggable targets: Promoting health by addressing the disease [published online ahead of print, 2021 Jun 11]. Biochimie. 2021;S0300-9084(21)00146-2. doi:10.1016/j.biochi.2021.05.019