Taking aim at NMSC: Nicotinic acid receptor potential therapeutic target in nonmelanoma skin cancer

December 1, 2009

Investigators have found that a particular nicotinic acid receptor has increased expression in later stages of SCC, indicating that this receptor may represent a target for therapy in nonmelanoma skin cancer.

Key Points

Tucson, Ariz. - Nicotinic acid receptors may represent another therapeutic target in nonmelanoma skin cancer.

"We have seen that nicotinic acid has a protective effect against skin cancer," explains Yira Bermudez, Ph.D., a post-doctoral fellow and research associate in the cancer center division at the Arizona Cancer Center/University of Arizona in Tucson, Ariz. "We have looked at the expression of nicotinic acid receptors in nonmelanoma skin cancer."

Dr. Bermudez noted that in preclinical studies, nicotinic acid has been shown to inhibit photocarcinogenesis and photoimmunosuppression induced by ultraviolet radiation (UV). She also noted that the mechanisms by which nicotinic acid exercises its protective effects are not well known.

Study analysis

She and co-investigators explored the mRNA and protein expression of HM74 and HM74A in skin cell lines; full-thickness skin reconstructs; and in normal, benign and malignant human skin tissues. They employed quantitative reverse transcriptase-polymerase chain reaction, Western blot and immunostaining analyses.

"What is interesting is that we found that the receptors are differentially expressed," Dr. Bermudez says.

Indeed, investigators observed that nicotinic acid receptors are expressed in epidermal keratinocytes at both the mRNA and protein levels, and the expression of both receptors is tremendously upregulated in immortalized and transformed cultured cells.

Investigators compared the relative levels of HM74 and HM74A message expression in normal skin to their message expression in squamous cell carcinoma (SCC) lesions.

They observed that both receptors are expressed in normal human skin, but the high-affinity nicotinic acid receptor, HM74A, is expressed at levels greater than twofold. That particular nicotinic acid receptor has increased expression in SCC, with an increase of up to roughly twentyfold, from stage I to stage III.

The expression of the other nicotinic acid receptor, HM74, is not altered in SCC lesions, from stage I to stage II. But with disease progression from stage IIB to stage III and the presence of more invasive disease, HM74 is significantly upregulated.

"The nicotinic acid effect in the skin appears to be mediated by nicotinic acid receptors," Dr. Bermudez says. "We see that there is increased expression of these receptors with progression (of SCC) to later stages. However, the function of the receptor is lost in malignancy. We believe the receptor may be acting as a tumor suppressor."

The results of the analysis suggest that nicotinic acid may represent a new therapeutic direction for the management and/or prevention of some skin cancers, such as SCC.

"These are preliminary data, but it may be that nicotinic acid can be available in a topical lotion or solution that can be used as a prophylactic therapy," Dr. Bermudez explains. "Our earlier data show that niacin drives formation of the skin barrier. A lotion may be used on its own or in conjunction with other therapies that are available."

Dyslipidemias

Nicotinic acid is key in the treatment of dyslipidemias, but its use has been limited due to adverse events. Derivatives have been developed that control the rate of topical delivery, eliminating the vasodilation effects.

Because of nicotinic acid's effect on the skin barrier, the nicotinic acid receptors may also represent a new therapeutic direction for the management of actinic keratoses, psoriasis, rosacea and other dermatological disorders where skin barrier is impaired or the therapy for the disease affects the skin barrier, Dr. Bermudez adds.

To date, investigators have not found the nicotinic acid receptors to be expressed in melanoma skin cell lines, according to Dr. Bermudez.

Human genetic variations in HM74 and HM74A have not been studied in detail, and the variations may affect the response to agents targeting receptors coded by the two genes.

Disclosure: Dr. Bermudez reports no relevant financial interests.