As reported by the Los Angeles Times, October 31, 2005.

Putting Cancer Cells to Sleep

Research is shedding new light on melatonin, a hormone that's produced at night.

Melatonin, long known to insomniacs as an over-the-counter sleep aid, is now being studied as a way to prevent and treat breast and other cancers.

Dubbed the "hormone of darkness," melatonin is made by the brain's pineal gland at nighttime. This summer, researchers at Brigham and Women's Hospital, led by epidemiologist Dr. Eva Schernhammer, showed that women who produced the least melatonin had a 70% higher chance of getting breast cancer than those with the most.

Schernhammer's group had previously shown that women who work at night are at higher risk of both breast and colon cancer. Light at night can shut off melatonin production.

Cancer epidemiologist Richard Stevens of the University of Connecticut Health Center in Farmington said that breast cancer rates were much higher in industrialized countries, where, among other things, people use artificial light at night, which dampens melatonin production.

"We can't say yet, but the evidence is accumulating that light at night, and the consequent decrease in melatonin, may be a major driver of breast cancer," Stevens said.

From an evolutionary point of view, melatonin may have developed as a signal to tell animals when to breed. In sheep, melatonin levels rise in the fall as the nights get longer and ewes become fertile perhaps as nature's way of ensuring that when they give birth four months later, the weather will be balmier.

Melatonin is also an important regulator of the circadian clock in the brain, which keeps the body on a regular cycle of wake and sleep. Light, be it from the sun or electric lights, suppresses melatonin production.

But when light disappears, and darkness falls, there's a cascade of nerve signals from the eye to the pineal gland, which then starts making melatonin.

That's why melatonin has been popularized as a sleep aid, although a 2004 government study found the pills on the market had limited effectiveness.

Frustrated by the high rates of breast cancer in industrialized countries, Stevens theorized in the late 1980s that light at night might drive cancer, and that melatonin might be protective.

"We know that if you take out the pineal gland in animals, that removes all melatonin, and then if you inject cancer cells, the cancer growth rate increases," said Steven Lockley, a neuroscientist at Brigham and Women's, who is studying blind women to see if they have higher than normal levels of melatonin, and whether they get less breast cancer. "We know that when you put an animal in constant light, that also stops all melatonin production, and you get a similar response. And if you then treat an animal with melatonin, you can slow down the cancer rate."

Researchers are starting to look at melatonin's treatment potential.

Dr. David Blask, a senior research scientist at the Bassett Research Institute in Cooperstown, N.Y., reported at a cancer meeting this summer that melatonin can "put cancer cells to sleep" by blocking their ability to soak up linoleic acid, which makes cancer cells grow rapidly. In animal studies, Blask said he has found that cancer cell growth is slower at night, when melatonin is highest, and faster during the day. He also found that adding melatonin to human breast cancer cells grown in rats can slow the cancer's growth.

In other animal studies, Steven Hill, vice chairman of structural and cellular biology at Tulane University in New Orleans, has found that melatonin binds to receptors on both normal and breast cancer cells. Once it lands on a receptor, he said, it acts on chemical signals inside the cell to suppress estrogen, which drives many breast tumors. "We can prevent 85% of mammary tumors in our rats with a combination of melatonin and retinoid [vitamin A]," he said.

In Europe, studies of people with cancer who are given melatonin are also promising, though preliminary. Melatonin seems able to not only slow cancer progression and improve survival in advanced cancer patients, but to protect healthy cells from the side effects of chemotherapy and radiation, said Dr. Fade Mahmoud, a clinical instructor at the University of South Dakota School of Medicine who published a review of the studies this summer.

Spanish researchers have shown that melatonin acts in human breast cancer cells much like drugs called aromatase inhibitors. This means it can prevent the body from converting the hormone testosterone into estrogen. Italian researchers, in a series of human studies, have shown that melatonin, which appears to have little toxicity, can boost survival at least modestly in some people with melanoma and cancers of the lung, breast, kidney and other organs.

These studies "sound intriguing," said Dr. Mark Pegram, director of the Women's Cancer Program at the Jonsson Comprehensive Cancer Center at UCLA. "But obviously more experimental studies are needed."

American researchers are also starting to pay attention to melatonin. With colleagues at a cancer research center in Zion, Ill., Dr. William Hrushesky, a senior clinician-investigator at the Dorn VA Medical Center in Columbia, S.C., is doing a randomized, double-blind study with melatonin plus chemotherapy to see if melatonin helps lung cancer patients.

Though it's too soon to rush out and buy over-the-counter melatonin to fight cancer, it is a good idea to "live a melatonin-friendly lifestyle," said Stevens.

That means going to bed earlier if you're a night owl, keeping the bedroom dark and the light dim in the bathroom if you make nightly trips there.

If you're a shift worker, ask your employer to explore changing the room lighting, more closely simulating normal night.

"The longer you stay in the dark," Stevens said, "the more melatonin you're putting out."