Tanning-like pigment response induced with topical small molecule


Researchers from Massachusetts General Hospital (MGH) and the Dana-Farber Cancer Institute (DFCI) have demonstrated a topical agent that induces a tanning response in cultured human skin, and without any ultraviolet (UV) light exposure.

In their paper, published in Cell Reports (June 13, 2017), the investigators note that a prior study from 2006 achieved eumelanin increase in red-haired mice, and showed that the increased pigment provided the mice with significant UV protection. However, the molecules used in that study were unable to penetrate the thicker barrier in human skin.

Cultured human skin treated for eight days with a small-molecule SIK inhibitor (right) shows a significant increase in pigmentation. Areas treated with a control substance (left) or an SIK inhibitor less able to penetrate human skin (center) show no darkening. (Nisma Mujahid and David E. Fisher, MD, PhD, Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital.

“The activation of the tanning/pigmentation pathway by this new class of small molecules is physiologically identical to UV-induced pigmentation without the DNA-damaging effects of UV,” says David E. Fisher, MD, PhD, in a press release. Dr. Fisher is chief of the Department of Dermatology at MGH and led both studies. “We need to conduct safety studies, which are always essential with potential new treatment compounds, and better understand the actions of these agents. But it’s possible they may lead to new ways of protecting against UV-induced skin damage and cancer formation.”

In the 2006 study, red-haired mice with a genetic variant that interrupts the signalling pathway to melanin production were treated with a topical agent called forskilin. This compound activates a protein further down the pigmentation pathway, bypassing the interruption and inducing production of eumelanin. However, tests of forskilin and a related compound in human skin were not successful.

The investigators then tried a different approach. A class of enzymes known as salt-inducible kinases (SIKs) are known to regulate the transcription of a protein even farther down the pigmentation pathway, and a Japanese research group had earlier shown that inhibiting SIK expression could activate pigmentation in mice.

However, Dr. Fisher and his team initially encountered similar results with the SIK inhibitors that they had with forskilin—while the red-haired mice experienced significant darkening within a few days, there was little response from the human skin models.

Dr. Fisher’s team turned for help to colleagues in the DFCI laboratory of Nathanael Gray, PhD, a co-author of the current study. Dr. Gray’s team developed a new class of small-molecule SIK inhibitors, better able to penetrate the thicker human skin, which were then tested by Dr. Fisher and his team. These were found to be better able to penetrate cultured human skin samples and induce significant darkening following eight days of daily, topical administration.

Microscopic examination of the treated skin samples confirmed that eumelanin was being produced and deposited near the skin surface in patterns typical to what is seen with UV-induced pigmentation or tanning, which the authors say suggests activation of the same pigmentation pathway.

“We are excited about the possibility of inducing dark pigment production in human skin without a need for either systemic exposure to a drug or UV exposure to the skin,” said Dr. Fisher.

#Tanning #Melanin #Eumelanin #Sunlesstanning #DrDavidEFisher #Saltinduciblekinases #MassachusettsGeneralHospital #DanaFarberCancerInstitute

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