For decades, scientists have had a hunch that zinc supplements could help prevent esophageal cancer, a particularly lethal malignancy that has been on the rise worldwide.

They've studied this essential nutrient in the lab, in populations around the globe, even in big clinical trials in China that gave dietary supplements to people at high risk of esophageal malignancy. The signs that zinc is protective have been intriguing, but inconsistent.

Now, however, new insights into zinc's role in gastrointestinal disorders - particularly acid-reflux disease - have renewed hopes that the pennies-a-day mineral could be therapeutic.

James Mullin, a professor at Lankenau Institute for Medical Research in Wynnewood, recently was granted a patent for the use of oral zinc to treat Barrett's esophagus, a complication of acid reflux that can progress to cancer. The institute is working with a company, Monk Street Partners, to commercialize a zinc lozenge aimed at preventing that progression.

Meanwhile, Eli Consumer Healthcare, a start-up company led by a Bucks County resident, already is producing its new zinc-based antacid for acid reflux, a problem that plagues a quarter of adult Americans and often defies standard prescription medications. TummyZen - slated for sale nationally in Target stores next month - is based on the research of Yale University gastrointestinal surgeon John P. Geibel, who showed that zinc reduces acid secretion in the stomach.

Zinc formulations - and there already are plenty on store shelves - are regulated as dietary supplements, so they don't go through the same rigorous approvals as prescription drugs.

Mullin and Geibel acknowledge that their studies don't prove conclusively that zinc will have the desired therapeutic effects.

Nonetheless, they see good reasons to try it.

"Barrett's is a disease with no drug therapy and no preventive approaches - no diet, no exercise, nothing," Mullin said. "We have a real basis to believe that this could work."

Grim prognosis

Studies have documented a global epidemic of the heart-burning, gut-churning misery that doctors call gastroesophageal reflux disease.

Proton pump inhibitors (PPIs), introduced in the 1980s, are the standard prescription therapy for severe reflux disease. The drugs block an enzyme that cells lining the stomach need to secrete acid. But in many cases, acid breaks through again. And PPIs can interfere with the absorption of some vitamins, minerals - including zinc - and medicines.

In up to 10 percent of acid-reflux patients, the chronic irritation leads to Barrett's. Experts hoped PPIs could reverse the damage, but most studies have been disappointing.

While relatively few people with Barrett's progress to cancer, those who do face a grim prognosis. The American Cancer Society estimates about 17,000 people will be diagnosed with esophageal cancer this year, and almost 16,000 will die of it.

A complex puzzle

Ten years ago, Mullin's lab began studying how zinc - naturally present in a wide variety of foods - fits into this complex puzzle of digestive disorders.

He had long researched the cells that line the gastrointestinal tract, which function as a protective barrier, regulating the passage of nutrients and other molecules. When these membrane cells move apart and become too leaky, they play a little-understood role in the development of cancer and other diseases.

"We and other labs were finding micronutrients that had the ability to reduce this leakiness," Mullin said.

Zinc seemed particularly promising. His team set out to investigate its effects on membrane permeability in a disease with well-defined stages - Barrett's esophagus.

But while listening to a lecture by Louise Fong, a professor of microbiology and immunology at Thomas Jefferson University, Mullin decided to "cut to the chase" and see whether zinc could ward off esophageal cancer.

Fong had done groundbreaking studies - in rats - that showed it could. She discovered that even mild zinc deficiency activates cancer pathways in the esophagus, promoting tumor formation. Replenishing zinc reversed precancerous changes. Zinc also altered the rats' microRNAs - genetic molecules that play a role in cancer by regulating cell division and death.

"I'm listening to Louise's talk and I thought, 'This lady has dramatic evidence that zinc on a daily basis in animals precluded the development of . . . esophageal cancer,' " Mullin recalled. "So [my lab] could either pursue the line of basic research, or go to the more important clinical question."

First, they had to show they could get enough zinc into Barrett's cells to have a measurable effect. This wasn't assured; they had already published a study showing PPI medications - taken by most Barrett's patients - reduced zinc absorption and storage.

To deliver the zinc right where it was needed, they gave Barrett's patients 26-milligram zinc gluconate lozenges to suck on twice a day for 14 days before having biopsies. Compared with a placebo lozenge, the zinc version boosted zinc levels and triggered molecular changes in the Barrett's cells.

The next step, underway now, involves enrolling 120 Barrett's patients to see how zinc changes their cellular microRNA profile. So far, Mullin said, the results are promising.

Working in a different way

While Mullin has focused on how molecules move in between digestive membrane cells, Geibel has unraveled how molecules use their electric charges to get in and out of those cells. He has discovered transport pathways in the stomach that are important to acid secretion.

Recognizing the drawbacks of PPIs - including that they can deplete zinc - Geibel wondered if boosting the mineral could suppress acid secretion.

In 2011, his team published results from a series of experiments in animals, as well as 12 healthy human volunteers.

The conclusion: "Zinc offers a novel rapid and prolonged therapy to inhibit gastric acid secretion in human and rat models."

Zinc turned out to reduce the membrane cells' secretion of an essential ingredient of digestive acid - namely, chloride ions.

"We were surprised and happy to see zinc was efficient," Geibel said. "Zinc stops the acid in a different way - it keeps chloride from getting out of the cells."

That study led to a patent and TummyZen. The product - 30 fast-dissolving 30-milligram caplets for about $9 - was hatched by a Yale program that matches promising faculty research with enterprising Yale business school students. One of them, Hasan Ansari of Levittown, is CEO of Eli Consumer Healthcare - and says on the website he uses TummyZen himself for heartburn.

There is a caveat: Experts have set the safe upper limit for zinc in healthy adults at 40 milligrams per day. Too much can cause vomiting and more serious toxicity. So even though zinc is widely available over the counter, the researchers advise against taking more than directed.

Weighing the benefits

Clinical trials are the gold standard of medical evidence, and the largest one ever undertaken on zinc and esophageal cancer underlines just how complex this issue is.

It was conducted in the Linxian region of China, where nutrition is poor, leading to zinc deficiencies, and rates of esophageal cancer are high. More than 3,300 people with precancerous esophageal abnormalities took a placebo or zinc-containing multivitamin from 1985 through 1991, then were followed for another 20 years.

The research team, which included scientists from the U.S. National Cancer Institute, reported in 2013 that supplements had no effect on total deaths, or deaths from any studied cause - including esophageal cancer.

Yet when researchers did a high-tech chemical analysis of biopsy specimens from a small number of the patients, they found high zinc levels were correlated with lower risk of esophageal cancer.

How could this be? Maybe, the researchers speculated, the zinc dose was too low, or the supplementation was too brief, or nutrients in the supplements interfered with the zinc, or the damage of chronic zinc deficiency can't be fixed late in life.

For Mullin, the possible benefits outweigh the unknowns.

"This is a prophylactic therapy that should be out there now, even before we've dotted all the i's and crossed all the t's," he said. "I can foresee a day when oral zinc will be used as an upper GI cancer-preventive, much like we use baby aspirin for colon cancer protection."

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