Compound in citrus oil could reduce dry mouth in head, neck cancer patients dog mouth sores pictures

The compound, called d-limonene, protected cells that produce saliva in mice exposed to radiation therapy — without diminishing the tumor-fighting effects of the radiation. The researchers, led by graduate student Julie Saiki, also showed that d-limonene taken orally is transported to the salivary gland in humans.

The finding was possible because of a close collaboration between clinicians and basic scientists, said co-senior author Daria Mochly-Rosen, PhD, professor of chemical and systems biology. This is a perfect example of two pieces that could not work alone.

About 40 percent of head and neck cancer patients who receive radiation therapy develop dry mouth, known clinically as xerostomia. It’s more than uncomfortable: patients struggle to speak and swallow and are more likely to develop oral pain or dental cavities, and the condition can lead to tooth removal in some cases, Le said.


And, although some recovery can occur in the first years after the therapy, once saliva production is impaired, it is usually gone for life.

Many of the saliva-producing cells that are needed to keep the mouth constantly moist are found in a pair of structures called the submandibular glands, tucked under the lower jawbone on each side of the chin. Radiation often kills these cells and, more troublingly, also salivary stem and progenitor cells, those juvenile members of the population that are needed to rebuild and restore the capacity to make saliva.

The key to retaining salivary function is protecting these rare but critical stem and progenitor cells. That’s tricky because, following radiation therapy, toxic, highly reactive compounds called aldehydes are created in the gland, gumming up cellular function.

Le, the Katharine Dexter McCormick and Stanley McCormick Memorial Professor, who specializes in treating head and neck cancer, said she had spent a decade hearing from her patients about their struggles with dry mouth. I wanted to do something, she said.

Her initial strategy was to try to regenerate salivary stem cells and, while working with these cells, her lab found that they contain high levels of an enzyme called aldehyde dehydrogenase 3A1, or ALDH3A1. The enzyme is a member of the large aldehyde dehydrogenase family of enzymes, proteins that initiate or speed up chemical reactions, that can defang troublesome aldehydes. But ALDH3A1 isn’t a match for the radiation-unleashed aldehydes on its own.

Le had met with Mochly-Rosen through SPARK, a program founded and co-directed by Mochly-Rosen, that shepherds basic science discoveries into the clinic. Mochly-Rosen, who is the George D. Smith Professor in Translational Medicine, had been working on aldehyde dehydrogenases for more than a decade and had obtained access to a library of 135 traditional Chinese medicine extracts.

Her team found that seven of these 135 extracts boosted ALDH3A1 activity. It was up to Saiki to see if she could break apart these complex natural extracts — from plants including tangerine, lotus and an Asian rhizome known as zhi mu in Chinese — to find out what, exactly, was activating the enzyme.

Admittedly, Mochly-Rosen and Saiki said, a bit of luck and a fair amount of trial-and-error were involved. D-limonene stood out from other compounds in the extracts because it is broken down relatively quickly in the body and has been deemed by the Food and Drug Administration as a food flavor generally recognized as safe that has been approved for use as a food additive, Saiki said.

A series of experiments with mouse cells that had been exposed to radiation showed that d-limonene reduced aldehyde concentrations in both adult and salivary stem and progenitor cells. Even when the cells were treated weeks after radiation exposure, d-limonene still improved their ability to recover, repair gland structure and produce saliva. Mice that ate d-limonene and were exposed to radiation also produced more saliva than mice that did not receive d-limonene and were exposed to radiation. The researchers also learned that d-limonene wasn’t likely to boost saliva production so high that mice, or humans, would be drooling — the compound didn’t increase saliva production in mice that hadn’t been exposed to radiation. And they confirmed that d-limonene did not affect tumor growth or interfere with the tumor-shrinking effects of the radiation in mice.

Buoyed by these positive results, the researchers wanted to know if the compound had any hope of helping patients. To work, it would have to be active inside the salivary glands. To find out, they launched a phase-0 study, an early clinical trial in a small number of patients to see if d-limonene, taken by mouth in a capsule, would be distributed to the salivary gland. Four participants who were having a salivary gland tumor removed took d-limonene for two weeks before the surgery. When the tissue was examined after it was removed, researchers found high levels of d-limonene, showing that it has the potential to be used therapeutically in humans — it reaches the salivary gland tissue.

Next, the team plans to start the clinical trial process, which will take several years and require a multi-institutional collaboration, Le said. If it works, then this type of drug would be used safely to prevent dry mouth in patients in the long run and make it much easier for patients to tolerate the radiation treatment with an improved quality of life after the treatment, she said.