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Biochemistry

Propolis against cancer

Synthetic compounds inspired on the resin from bees are effective in the treatment of tumors

MIGUEL BOYAYANThe capacity of propolis, a resin produced by bees, to seal and to sterilize hives is already well-known to science. Several studies also indicate that the substance has antiseptic, healing, antimicrobial, anti-inflammatory and antioxidant powers, amongst others. In the knowledge of this, a team of Brazilian researchers, led by Cuban chemist José Agustín Pablo Quincoces Suárez, a professor from São Paulo’s Bandeirante University (Uniban), has synthesized in the laboratory chemical compounds similar to those found in propolis, with the objective of studying them and, in the future, of using them in the formulation of medicines. The research, which started seven years ago, proved to be promising, and the first results are beginning to appear. A family of compounds was seen to be highly effective in the treatment of human cancer cells in tests in vitro and on laboratory animals. “The results are heartening, and show that we are on the right path. We have now filed two patents referring to the methods for obtaining the substances, to the compounds themselves and their applications”, points out Quincoces.

To arrive at this stage of the research, though, was not at all easy. The first challenge was precisely to manage to produce compounds similar to those existing in propolis. To do so, the researchers used as raw material chemical inputs based by the food and drugs industries. After much experimenting, five families of compounds – baptized with the letters HB, L, Q, V and HMF – showed signs of being promising. But one question is in keeping: if these substances are found in nature, why synthesize them in the laboratory? The answer is simple. As these compounds are present in very low concentrations in propolis, in the order of micrograms or milligrams, they would be insufficient for carrying out pharmacological studies and, depending on the results, for producing medicines. Furthermore, by being produced in the laboratory, these substances can have their properties improved by means of computer modeling techniques. “In some cases, we altered their original structure, to arrive at a more efficient molecule, either with an increase of its biological activity, or with a reduction in its toxicity”, explains pharmacist Daniela Gonçales Rando, a researcher from the group at Uniban.

The next step after the synthesis in the laboratory was to start tests with the different compounds, in order to gauge their therapeutic activities. For this, the group established partnerships with various research institutions in Brazil and abroad. The first tests with the HB family of compounds started in 2001 at the Pluridisciplinary Center for Chemical, Biological and Agricultural Researches (CPQBA) at the State University of Campinas (Unicamp). “Antitumor and antimicrobial tests were successfully carried out in vitro, and toxicological tests in vivo, on animals. In the following year, researchers from the Immunology Laboratory of the Federal University of São Paulo (Unifesp) began to do antitumor testing with compounds from the V family”, reports Quincoces, who is the coordinator of Uniban”s Organic Synthesis Laboratory.

In that same year, immunologist Durvanei Augusto Maria, from the Butantan Institute, in São Paulo, joined the group and began to carry out a battery of antitumor and toxicity tests of compounds from the HB family. These tests showed that the substance was capable of preventing the progression of tumors of one type of melanoma, a kind of skin cancer, in mice.

The good news is that the results were positive even when the dose injected was in a quantity far lower than that used by antitumor drugs available on the market. Another aspect was that the substance inhibited the occurrence of metastasis. “We have evidence, not yet proven, that the compound induces cell death by apoptosis, the so-called “cell suicide””, says Quincoces. “Furthermore, we noticed that the cancer cells were eliminated without any damage to the healthy cells, unlike what happens with the majority of medicines for the treatment of cancer.” These facts were proven by means of histopathological studies (analyses of lesions) of organs and tissues carried out by Professor Paulo Pardi, from Uniban.

Another line of the research is conducted by biophysician Clizete Sbravate Martins, an independent researcher and a former coordinator of the biomedicine course at Uniban. She took charge of the antiparasitic tests with the phenolic compounds of the HB family, which began to be carried out at Uniban’s research laboratories, and later in the Parasitology Department of USP’s Biomedical Sciences Institute (ICB). “The parasite tested was the one that causes leishmaniasis, a serious disease with an important incidence in poor countries. We carried out test in vitro and in vivo and noted a very marked effect of the compound. While in the untreated infected mice there was an 80% increase in the size of the cutaneous lesion – one of the manifestations of the disease -, in the treated animals no progression of the lesion was recorded”, the researcher says. These results are important because the only medicines approved for the treatment of  leishmaniasis are toxic.

Antitumor tests
The work is also able to count on the cooperation of researchers from the University of the South of Santa Catarina (Unisul), responsible for the testing in vitro relating to the analgesic and anti-inflammatory properties of the compounds. In this strand of the research, excellent results are being observed. At the Ludwig Boltzmann Institute for Clinical Oncology, of the University of Vienna, in Austria, Professor Gerhard Hamilton is carrying out antitumor tests with compounds from the L, Q and HMF families. “They have now achieved excellent results in studies in vitro for various types of tumor, with head and pancreatic cancers, which are fatal”, explains Quincoces.

Despite the good results achieved so far, a long road still has to be covered for the substance to be transformed into a medicine. The team needs to conclude the pharmacokinetic studies, relating to the absorption of the compound by the organism and to the form of administration, which are studies in directed formulation, to reveal the exact action mechanism of the compound in the organism and to carry out tests on other animal species. The group estimates that within one or two years these stages will be concluded and the tests on humans may be started, another fundamental stage of the research. “We are in conversations with a national manufacturer of medicines and with a research institute, the names of which we cannot reveal, who were interested in carrying out clinical tests and in the production of the medicine”, says Quincoces.

The projects
1. Synthesis of prenylated heterocycles from natural products (nº 04/11351-0); Modality Regular Line of Research Grants; Coordinator José Agustín Quincoces Suárez – Uniban; Investment
R$ 95,804.46 and US$ 22,380.94 (FAPESP)
2. Antiparasitic properties of 1.5-bis (4-hydroxy-3-methoxy-phenyl)-penta-1.4-dien-3-on and its byproducts (nº 04/11352-6); Modality
Intellectual Property Support Program (Papi); Coordinator José Agustín Quincoces Suárez – Uniban; Investment R$ 9,500.00 (FAPESP)
3. Antitumor properties of 1.5-bis (4-hydroxy-3-methoxy-phenyl)-penta-1.4-dien-3-on and its byproducts (nº 01/10383-7); Modality Intellectual Property Support Program (Papi); Coordinator José Agustín Quincoces Suárez – Uniban; Investment R$ 58,261.39 (FAPESP)

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