In a study conducted at the Butantan Institute, one of the toxins that make up rattlesnake venom (Crotalus durissus terrificus), The crotoxin had a modulatory effect on the immune system in the presence of cancer.
The action of the toxin on macrophages, the body's defense cells, indicates a possible path for future immunotherapies. In this type of treatment, substances are used or changes are made to the cells of the immune system to induce them to fight tumors more efficiently.
The study was published in the magazine Toxins and had the collaboration of researchers from the University of São Paulo (USP) and the University of Ribeirão Preto (Unaerp).
“Cancer-bearing mice that received a small, single dose of the toxin showed a prevalence of macrophages that release crucial substances to destroy tumor cells, such as nitric oxide,” he says. Camila Lima Neves first author of the work, carried out during the master's degree in the Postgraduate Program in Sciences-Toxinology at the Butantan Institute.
More than demonstrating the effects of crotoxin on tumors, the results of this study highlight how the “reeducation” induced by the toxin on the macrophage profile can be a way to acquire a sufficient and long-lasting antitumor immune response, reinforcing the importance of immunotherapy.
In the study, administration of crotoxin to animals with ascitic tumors led to the prevalence of M1 macrophages, a pro-inflammatory profile more suitable for inhibiting the development of tumors, while M2 macrophages, a profile that favors the tumor, were reduced.
“We are studying structural forms and combinations of crotoxin to find one that is less toxic and more effective in its immunomodulatory and antitumor effects. But it is possible that other structures of the crotoxin molecule, including already known ones, can perform the same action or enhance its effect”, he adds. Sandra Coccuzzo Sampaio researcher at the Butantan Institute and coordinator of the study, which is part of the project supported by FAPESP.
To arrive at the results, the researchers followed two groups of mice for 13 days. The first group received an inoculation of ascitic tumor cells, a liquid tumor that develops in the abdominal region.
The animals were then divided into three treatments: a saline solution (control group), a small dose of crotoxin (0.9 micrograms per animal) and a larger dose of the toxin (5 micrograms per animal).
The second group was healthy animals that received only the three treatments, in order to demonstrate the effect of the toxin on an organism without cancer.
Activated defense cells
At the end of the 13th day of experiments, the administration of the lowest dose of the toxin (0.9 micrograms) in animals with ascitic tumors led to the prevalence of M1 macrophages (antitumor) in around 60%, which was the same percentage of cells found in animals that did not have a tumor. The result shows that the treatment was effective in maintaining these defense cells in the tumor microenvironment.
The higher dose, in turn, led to an increase in M1 macrophages and a decrease in M2 macrophages, demonstrating the ability of this toxin to prevent cells that favor the tumor.
On the sixth day after treatment with different doses of crotoxin, the tumor volume had significantly decreased in the cancer-bearing mice, when compared to the group that received only a saline solution. However, from this period until the end of the experiment, only the group that received the lowest dose was able to reduce tumor volume, by 27%.
In animals treated with the lowest dose of the toxin, after six days of tumor inoculation, a reduction in the total number of tumor cells and an increase in the number of leukocytes, which are also defense cells, were observed in comparison to those that received saline solution.
“This shows that the lowest dose is sufficient to modulate macrophages and reduce the tumor. This data is extremely relevant, as the antitumor effects of crotoxin are known due to the direct action of the toxin on tumor cells. Through studies in vitro and from this work, we were also able to demonstrate the importance of the immunomodulatory action of crotoxin on macrophage phenotypes, critical for tumor control. Hence the need to research new combinations and reduce possible toxic effects of the molecule on the body”, explains Coccuzzo.
The lowest dose of the toxin, at the end of the 13th day of treatment, also provided a 35% increase in the production of nitric oxide by macrophages in mice with tumor, compared to the control group, without toxin. The one who received the highest dose of crotoxin had no changes in this parameter. Nitric oxide is an important free radical in the defense against tumors, as it penetrates the tumor cell and leads to its destruction.
“This is the first work demonstrating how a single administration of crotoxin interferes with the reprogramming of macrophages, favoring the most desired profile when the tumor is installed, as it controls tumor progression events”, says Neves.
“A strong piece of evidence that we observed in this work was the inhibitory action of crotoxin on tumor volume and the number of tumor cells, in addition to stimulating the production of pro-inflammatory mediators, crucial for the anti-tumor action of macrophages”, concludes Coccuzzo.
The full article Crotoxin Modulates Macrophage Phenotypic Reprogramming is available at: www.mdpi.com/2072-6651/15/10/616 .
Source: CNN Brasil
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