Bush “kills horse” and its possible treatments against tumors

It is a small South American shrub that naturally extends from Mexico to Argentina. It is so toxic that it is popularly known as “horse killer” or “horse burst”, but it contains a compound that sheds light on a possible approach to developing new treatments against certain types of tumors, according to a study conducted by Argentine scientists and published in the journal Drug resistance updates.

With the objective of identifying new molecular targets for the treatment of cancers with a deficiency in the activity of the BRCA2 gene – such as those of the ovary, breast and colon – that resist standard therapy, the group led by the physician in Cellular Biology Gastón Soria searched in typical plants from Argentina the presence of molecules with the capacity to become future drugs. And they found not only a compound with high efficacy in experimental models, but also the enzyme on which it acts to slow down the advancement of tumor cells.

Use local extracts

A differential of our strategy, since its inception, was to use extracts derived from plants in our country as a source of induction of synthetic lethality.”, explained Soria, an entrepreneurial scientist who co-founded the company OncoPrecision. And he said that for this they partnered with specialists in natural products.

We tested approximately 100 compounds that were purified over decades of research work in the laboratory of PhDs in Chemistry Viviana Nicotra and Manuela García, from the Multidisciplinary Institute of Plant Biology at the National University of Córdoba (UNC).”, pointed Soria.

The most promising turned out to be solanocapsin, an alkaloid isolated from the “killer horse”, Solanum pseudocapsicuman ornamental plant very well known in our country, not only for its beauty, but also for its very high toxicitySoria said. In several countries it is known as the Jerusalem cherry, but in Argentina, popular knowledge baptized it in a less romantic and more explicit way: “kills horse” or “takes horse”. In this sense, it is evident that no patient should consume the plant directly.

Synthetic lethality of the “killer horse”

According to the researchers, the action of solanocapsin present in “horse matador” fits into a type of strategy that the pharmaceutical industry is seeking to develop therapies for “selective toxicity”, that is, targeted at specific genetic mutations that are expressed only in cancer cells and are not present in healthy ones, which reduces adverse events. It is known as “synthetic lethality”.

Synthetic lethality aims to find drugs that take advantage of tumor genetic alterations as an Achilles heel”, summarized Vanesa Gottifredi, PhD in Chemistry, head of the Cell Cycle and Genomic Stability Laboratory at the Leloir Institute Foundation (FIL) and another co-author of the work. It’s based on the principle that although healthy cells may have genes that don’t do their job well, they usually don’t suffer pathological consequences because their job tends to be compensated for by others, she explained.

However, when a combination of deficiencies occurs in which a function is lost and also the compensatory or surrogate function, then the cell dies. In other words, there could be two genetic abnormalities that, when occurring independently, are not lethal, but become lethal when combined in the same cell.

Suppose that gene 1 is BRCA2, the loss of which can be inherited in families, as happened to Angelina Jolie. And that a pharmaceutical laboratory finds a drug that inactivates gene 2 that compensates for it. For the patient who has gene 1, the drug does nothing, but for the tumor that has developed due to the loss of that gene 1, the drug kills it.”, Gottifredi wrote.

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A door that opens with the “killing horse”

In its native format, solanocapsin showed greater toxicity in cells deficient in the BRCA2 gene, which made us think about its potential as a precursor structure of a drug, something that had not been proposed until then. This selective toxicity was exactly what we were looking for.”, described Soria. “Thus, we developed semi-synthetic derivatives and focused on finding their possible molecular target in tumor cells, assuming that in this way we could open new therapeutic opportunities for patients.’ he added.

Second phase of the investigation

A later stage of this work was carried out with Cellzome, a German laboratory owned by GlaxoSmithKline (GSK), the British multinational pharmaceutical company that has largely funded this advance through its program Trust the Science. With them, several studies were carried out aimed at discovering which proteins solanocapsin bound to inside cells and, consequently, detecting those possibly responsible for the observed selective toxicity action. “The five most active proteins were identified and what called attention was the fact that solanocapsin binds with high affinity to the dCK enzyme, which made us think that it could be inhibiting it.”, said Soria.

As there were no commercial inhibitors of this enzyme to validate the hypothesis, Soria sought out Caius Radu, a researcher at the University of California at Los Angeles (UCLA), United States, who led the only group in the world that had so far developed an inhibitor for dCK, in time in an in vitro experimental phase. “Your participation in this work was fundamental because it allowed us to demonstrate that dCK is indeed the molecular target that triggers selective toxicity in BRCA2 cells.”, emphasized Soria. And he also highlighted the role of Gottifredi’s group in FIL, “which helped demonstrate, among other things, that the mechanism of action of solanocapsin is substantially different from that of PARP inhibitors, currently standard therapy”.

The possibilities for the future

Asked about what’s to come, the Argentine was enthusiastic: “The possibilities for the future are many. On the one hand, he said, there is the possibility of assessing dCK inhibition directly in patient samples. On the other hand, now the pharmaceutical industry has convincing evidence to invest in the design of more potent and safer dCK inhibitors with clinical potential.”.

Research on the “killing horse” was carried out under the auspices of the Scientific and Technological Research Fund (FONCYT) of the Ministry of Science, Technology and Innovation of Argentina and the trust science, a GSK public-private cooperation initiative to support pre-competitive research in Latin America and reinforce the training of highly specialized human resources in the country, with the aim of developing projects of high scientific value and with the potential to generate transferable products for the productive sector sector.

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