Compound blocks the advance of melanoma

Pre-clinical tests carried out at the Universidade de São Paulo (USP) revealed that a compound extracted from pariparoba (Pothomorphe umbellata), a bush native to the Atlantic Rain Forest, is capable of inhibiting the development of melanoma and preventing tumor cells from invading the deepest layer of the skin and spreading to other tissues.

By Karina Toledo

Agência FAPESP – Pre-clinical tests carried out at the Universidade de São Paulo (USP) revealed that a compound extracted from pariparoba (Pothomorphe umbellata), a bush native to the Atlantic Rain Forest, is capable of inhibiting the development of melanoma and preventing tumor cells from invading the deepest layer of the skin and spreading to other tissues.

The molecule, 4-nerolidilcatecol (4-NC), was tested in an artificial skin model during the doctoral studies of Carla Abdo Brohem at the Department of Clinical Analyses of the School of Pharmaceutical Sciences (FCF-USP), with FAPESP funding.

The team has already begun the animal testing phase. The results were published in Pigment Cell & Melanoma Research magazine.

According to study coordinator Silvya Stuchi Maria-Engler, melanoma is the most aggressive form of skin cancer and originates in pigment-producing cells called melanocytes. Data from the scientific literature show that 20-25% of all cases diagnosed are fatal.

“If treated in the initial phase, the chances of recovery are high. But once it has metastasized, the survival period is short, around 8 months, because the tumor is very resistant to existing drugs. New medications, however, are very welcome,” she said.

The 4-NC compound, found in the extract of pariparoba root, had already shown potent antioxidant effects in previous studies, where it protected the skin from damage caused by solar radiation. That study, also financed by FAPESP, was coordinated by Silvia Berlanga de Moraes Barros at FCF-USP. In 2004, a gel formula containing pariparoba root extract was patented for cosmetic use in the prevention of skin cancer.

Later tests on tumor cell cultures showed that 4-NC could induce cellular death. “Even if it isn’t effective against melanoma in the other stages of research, the compound has many positive qualities. We can evaluate it against other types of cancer,” said Stuchi.

Now, in the 3D-skin model, 4-NC impeded tumor cells from migrating from the epidermis to the dermis. “The molecule has already been through toxicity exams in animals. If it also passes the effectiveness evaluation, it could be tested on humans,” said Berlanga.

Click below to watch a video on the study.*

Developments

The artificial skin used in the experiment is the result of the project “Generation of artificial human skin and invasive melanomas as a platform for pharmacological testing,” coordinated by Stuchi and financed by FAPESP.

“We call it artificial, but it’s actually human skin reconstructed in the laboratory,” she explained. Everything begins with a fragment of skin donated from plastic surgery and received by the team thanks to partnerships with the USP University Hospital and the Hospital das Clínicas.

The scientists then isolate the skin’s main constituents—fibroblasts, keratinocytes and melanocytes—and store them in a biobank. “When we need to test a new molecule, we re-assemble these elements and build skin very similar to human skin,” told Stuchi.

In addition to the studies with 4-NC, the research has other potential applications. In one study, immune system cells are being added to the artificial skin model, making it more complete. “This way, aside from testing the toxicity and effectiveness of a new compound, we can evaluate whether or not it has the potential for causing allergy or irritation,” she explained.

In another part of the study, the researchers simulate the conditions of aged skin in vitro. “As the years pass, glucose residue is deposited on the proteins—collagen, for example. This disorganizes the extracellular matrix that composes the dermic layer of the skin, causing wrinkles and flaccidity,” said Stuchi.

This problem, she added, is more evident in diabetes patients and makes wound healing more difficult. The aged-skin model, however, will allow the action of anti-wrinkle cosmetics and medication for the skin of diabetic patients to be tested.

“Our long-term goal is to do skin transplants to treat chronic wounds and burns,” she said. The FCF-USP team is also studying the development of melanoma in the aged-skin model and in the immunocompetent-skin model.

In addition to the tissue being much more similar to human skin, the studies carried out on artificial skin also carry the advantage of using fewer research animals. In the case of cosmetics, it is possible to completely eliminate animal testing.

In Europe and the United States, artificial skin kits are sold to the cosmetic and pharmaceutical industries. In Brazil, companies need to send their molecules to be tested abroad, even though the country already has the technology.

“We have been approached by a number of companies, but we don’t have the means to perform this service routinely. In order to do so, a large investment in equipment and training of professionals would be necessary,” said Stuchi. Currently, the team has a partnership with Johnson & Johnson to evaluate the effectiveness and safety of their health products.

*ShockWave Flash file. In case you cannot open this file, access the video at: www.youtube.com/watch?v=1GU36JmXxqo