Karina Toledo | FAPESP Agency – After revealing in a pioneering way the potential of the Zika virus to combat brain tumors, a group from the State University of Campinas (Unicamp) led by professor Rodrigo Ramos Catharino showed that the pathogen can also be a weapon against prostate cancer.
Through experiments carried out with a human prostate adenocarcinoma line (PC-3), scientists observed that Zika, even after being inactivated by high temperature, is capable of inhibiting the proliferation of tumor cells. The search results, supported by FAPESP, were disclosed in the magazine Scientific Reports.
“The next step in the investigation involves testing on animals. If the results are positive, we intend to seek partnerships with companies to make clinical trials viable”, said Catharino, professor at the Faculty of Pharmaceutical Sciences at Unicamp and coordinator of the Innovare Biomarkers Laboratory.
The line of research coordinated by Catharino began in 2015, when the relationship between the Zika epidemic and the increase in cases of microcephaly in the Northeast states was discovered. After studies confirmed the pathogen's ability to infect and destroy neural progenitor cells - which in developing fetuses give rise to different types of brain cells - the researcher planned to test the virus on glioblastoma lines, the most common and aggressive type of cancer. of the central nervous system in adults (Read more at agency.fapesp.br/26991).
The good results observed vitro by the Unicamp group were confirmed in an animal model by scientists from Human Genome and Stem Cell Research Center (CEGH-CEL), a Research, Innovation and Diffusion Center (CEPID) supported by FAPESP at the University of São Paulo (USP) (Read more at: agency.fapesp.br/27676).
“As the sexual transmission of Zika has also been confirmed and the virus's preference for infecting reproductive cells, we now decided to test its effect against prostate cancer,” he told FAPESP Agency Jeany Delafiori, doctoral student under the supervision of Catharino.
The work has been conducted with the support of the Center for Research on Obesity and Comorbidities (OCRC), a FAPESP CEPID at Unicamp.
Persistent inflammation
In study disclosed recently, also in Scientific Reports, Catharino's group discovered that markers of neurological inflammation could be found in the saliva of babies born with microcephaly – and whose mothers were diagnosed with Zika during pregnancy – until at least two years after birth.
“This showed that this pathogen induces inflammation that lasts for a long time, even after its complete elimination from the body. In the 'wild' version [without going through the inactivation process], therefore, the virus could bring undesirable effects and could not be used as therapy”, explained Catharino.
The researchers then decided to test whether even after inactivation Zika would maintain the ability to destroy tumor cells. The experiments were carried out with a viral strain obtained from samples isolated from an infected patient in Ceará, in 2015. After cultivation in the laboratory, the virus was fused to a nanoparticle and heated to a temperature of 56º C for one hour, with the in order to inhibit the potential to cause infection.
The next step was to place a culture of PC-3 cells (prostate adenocarcinoma) in contact with the inactivated virus and, after 24 and 48 hours, compare it with another group of tumor cells not exposed to the pathogen.
“We observed a selective cytostatic effect [inhibition of cell reproduction] for PC-3 cells. In the analysis carried out after 48 hours, the strain that was in contact with the inactivated virus showed 50% lower growth than the control strain”, said Delafiori.
To discover how Zika altered the metabolism of tumor cells, the culture material was analyzed using a mass spectrometer – a device that works like a molecular balance, that is, it allows the separation and identification of elements present in biological samples according to mass.
Then, with the aim of making sense of the large volume of data obtained by spectrometry, a multivariate statistical analysis known as PLS-DA (partial least squares discriminant analysis) was carried out, which revealed 21 markers capable of describing how the virus affects the metabolism of the tumor cell and inhibits its proliferation.
“We found, for example, lipid markers involved in stress conditions and in the process of cell death, such as ceramides and phosphatidylethanolamines. These and other reported markers reflect the lipid remodeling induced by the particle and the impairment of metabolism pathways for molecules such as porphyrin and folic acid, which would contribute to cellular stress and the observed antiproliferative effect,” said Catharino.
According to the researcher, the set of 21 metabolites can help both in understanding the biochemical changes induced by the virus and in the search for therapeutic targets, paving the way for several new studies.
In addition to Delafiori, the research included the participation of scholarship holder PhD from FAPESP Carlos Fernando Odir Rodrigues Melo, also guiding Catharino.
The article Molecular signatures associated with prostate cancer cell line (PC-3) exposure to inactivated Zika virus, by Jeany Delafiori, Estela de Oliveira Lima, Mohamed Ziad Dabaja, Flávia Luísa Dias-Audibert, Diogo Noin de Oliveira, Carlos Fernando Odir Rodrigues Melo, Karen Noda Morishita, Geovana Manzan Sales, Ana Lucia Tasca Gois Ruiz, Gisele Goulart da Silva, Marcelo Lancellotti and Rodrigo Ramos Catharino, can be read at www.nature.com/articles/s41598-019-51954-8.
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