Study shows how melatonin can inhibit breast cancer

Hormone that regulates sleep and wakefulness cycles in mammals acts in controlling the formation of new blood vessels in tumors, according to a study led by Brazilians, published in PLOS One.

By Elton Alisson

Agência FAPESP – In addition to regulating the cycles of sleep and wakefulness, melatonin – the hormone naturally produced by mammals in the pineal gland of the brain in response to darkness – may help slow the growth of breast cancer.

A study conducted by scientists at the São José do Rio Preto School of Medicine (Famerp) in collaboration with colleagues at the Henry Ford Hospital in Detroit, Michigan, and published in January in the journal PLOS One, has shown that this ability of the hormone is due to the role it plays in controlling the formation of new blood vessels from the existing vascular structure of the tumor in a process known as angiogenesis.

The study was carried out as part of the project, “Angiogenesis evaluation in response to treatment with melatonin in breast cancer: a study in vitro and in vivo,” funded by FAPESP.

“We determined that melatonin is able to inhibit tumor growth and the production of cancer cells, in addition to blocking the formation of new blood vessels in the tumors of model animals [in vivo] and cells [in vitro],” Debora Aparecida Pires de Campos Zuccari, Famerp professor and project coordinator, told Agência FAPESP.

According to Zuccari, it is known that melatonin, when administered in therapeutic doses – above the levels naturally found in the body – shows antioxidant properties. Thus, it is expected that the hormone can suppress the growth of some types of cancer cells, especially when combined with certain drugs used to treat cancer. Melatonin is not sold in Brazil, but it is marketed as a food supplement in countries such as the United States.

In order to test these hypotheses, in 2008, Zuccari began a series of studies to determine whether melatonin could slow breast cancer, which is the most common type of cancer in women, and whose high mortality rate is due mainly to its progression and metastasis (propagation of cancer cells; read more at http://agencia.fapesp.br/en/17563).

According to the researcher, the tumor growth is associated with angiogenesis – the formation of new blood vessels from the tumor’s existing vasculature – regulated by genes such as hypoxia induced transcription factor (HIF-1α), vascular endothelial growth factor (VEGF), platelet derived growth factor (PGFF), epidermal growth factor (EGF) and angiogenin.

Once the tumor begins the process of exponential growth and attains several millimeters in diameter, the center of the tissue begins to experience a lack of oxygen (hypoxia), which stimulates the expression of the genes responsible for angiogenesis, mainly VEGF, to increase the supply of nutrients to the site, Zuccari explained.

“The VEGF bonds to its receptors and in this way promotes angiogenesis through its capacity to stimulate the growth, migration and invasion of endothelial cells (located in the internal cell layer of the blood vessels),” said the researcher.

“Since revascularization is essential for the growth of tumors and metastasis, controlling angiogenesis is a promising strategy for limiting the progression of cancer,” she indicated.

Study in mice

In order to evaluate the effects of melatonin on angiogenesis in breast cancer, the researchers conducted a study with athymic nude mice: genetically modified hairless rodents. To carry out the study, researchers implanted tumor cells in the mammary glands of a group of these immunodeficient animals.

The mice received intraperitoneal injections of 1 milligram (mg) of melatonin for 21 consecutive days, one hour before the room lighting was turned off.

Tumor volume was measured weekly using a digital caliper. At the end of the experiment, the animals underwent single photon emission computed tomography (SPECT) scanning to determine whether the melatonin had contributed to reducing the size of the tumor and whether there had been a change in the formation of new blood vessels.

The researchers found that the mice treated with melatonin showed reduced tumor size and cell proliferation after 21 days of treatment, compared to the control animals that received no hormone. They also noted a reduction in the density of the tumor blood vessels of the group treated with melatonin.

“Treatment with melatonin proved to be effective in reducing tumor growth and cell proliferation as well as in the inhibition of angiogenesis,” said Zuccari. According to her, the study has been replicated on tumor cell lineages.

The findings of the analyses indicated that melatonin administered in therapeutic doses is able to reduce the viability of cancer cells. Expression of the angiogenesis receptor VEGFR 2 also decreased significantly in the animals treated with melatonin compared to the control group, said Zuccari.

“We demonstrated that the effectiveness of the VEGF bond with the angiogenesis receptor [VEGFR 2] diminished when melatonin was used,” explained the researcher.

Next steps

According to Zuccari, she and her group are in the process of completing a study in which they are assessing the role of melatonin in reducing metastasis of breast cancer cells.

Preliminary findings have also indicated a significant reduction in the focus of the metastasis in mice that received injections of the hormone. “We’re trying to show that there are several fronts on which the melatonin can act, and the hormone is effective in all of them,” she noted.

After completing the animal studies, the plan is to conduct clinical studies (on humans) using melatonin. One major obstacle to this, however, is that because the action has not yet been proven in treating cancer, the hormone cannot be used on patients who have another therapeutic possibility.

“We would have to begin the clinical treatment with a group of terminal patients who have no other treatment options, to determine, initially, whether melatonin improves their well-being, so that later we could analyze other issues such as if it inhibits the progression of cancer,” Zuccari explained.

The researchers have begun a study on women in the same age group with and without breast cancer to test the hypothesis of whether women with cancer have lower levels of melatonin in their bodies than women without cancer.

“If this hypothesis is confirmed, perhaps it is because these women with breast cancer are unable to obtain the protective effects of melatonin and would need to supplement their diets with it,” said Zuccari.

The article “Effect of melatonin on tumor growth and angiogenesis in xenograft model of breast cancer” (doi: 10.1371/journal.pone.0085311) by Zuccari and colleagues is available in the journal PLOS One at www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085311.