Way back in 2006, scientists discovered a compound that could induce skin tanning in mice without exposing them to cancer-causing UV light. Now, after 11 years and ongoing trial-and-error, those scientists have reworked their approach to trigger the same response in cultured human skin, something that could make for a safer way for sun-worshippers to achieve a bronzed look.

The initial discovery was made by researchers at the Dana-Farber Cancer Institute (DFCI), who found that by giving specially-engineered mice a compound called forskolin, which is derived from the root of the forskohlii plant in India, they could make them tan without exposure to sunlight.

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The mice in question were red-haired and engineered to mimic fair-skinned humans, with a genetic variant that interrupted the pathway leading to the production of the dark melanin pigment. This meant that the animals tanned poorly, but what the researchers found was that the forskolin activated a protein further down the pathway which induced a dark pigment called eumelanin, in effect bypassing that interruption.

Turning their attention to humans, the researchers hit numerous roadblocks. Testing of forskolin on human skin samples was unsuccessful, most likely because it is around five times thicker than that of mice. Subsequent experiments using a salt-inducible kinases (SIK) inhibitor, which had been shown previously to trigger pigmentation in mice, were successful in the red-haired mice, but again fruitless in humans.

Now, researchers at DFCI together with Massachusetts General Hospital have developed a new class of small molecule SIK inhibitors that are optimized to penetrate the thicker human skin and induce the expression of a gene called MITF. This gene provides the instructions for a protein that controls the development of pigment-producing cells called melanocytes.

Following eight days of daily topical administration, the team found that the inhibitors induced significant darkening in cultured human skin samples (seen above on the right). And under the microscope, it observed that the treated samples showed the eumelanin pigment had been produced and deposited near the skin surface.

This is key, because it is the same thing that happens when pigmentation occurs through tanning, which indicates that the very same pigmentation pathway has been activated but with one key difference. UV light tans the skin by first damaging the DNA and causing the pigment-producing melanocytes to divide, something that also causes skin cancer. So in effect, this new class of inhibitors appears to induce the same tanning effect, minus the damage.

"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 Fisher, chief of the Department of Dermatology at Massachusetts General Hospital and leader of the study. "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."

The team's research was published in the journal Cell Reports.

Source: Massachusetts General Hospital

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