A small South American shrub that extends naturally from Mexico to Argentina and is so toxic that it is popularly known as “horse-killer” or “horse-buster”, it treasures a compound that could help develop new treatments against certain types of tumors.
This has been determined in a new study, led by Argentine scientists and published in the academic journal Drug Resistance Updates.
With the aim of identifying new molecular targets for the treatment of cancers deficient in BRCA2 gene activity (such as ovarian, breast and colon cancers) that are resistant to standard therapy, the group led by PhD in Cellular Biology Gastón Soria sought in typical plants of Argentina the presence of molecules with the capacity to become future drugs. And not only did it find a compound with high efficacy in experimental models, but also the enzyme on which it acts to slow down the advance of tumor cells.
“A differential part of our strategy, from its inception, was to use extracts derived from plants from our country as a source of synthetic lethality induction,” Leloir Soria, an entrepreneurial scientist who co-founded the company OncoPrecision, explained to the CyTA Agency. And he said that for that they partnered with experts in natural products.
“We tested approximately 100 compounds that were purified over decades of research work in the laboratory of Chemistry doctors Viviana Nicotra and Manuela García, from the Multidisciplinary Institute of Plant Biology of the National University of Córdoba (UNC),” he said. Soria.
The most promising turned out to be solanocapsin, an alkaloid isolated from Solanum pseudocapsicum, “a well-known ornamental plant in our country, not only for its beauty but also for its extremely high toxicity,” Soria 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: “revientacaballo”. In this sense, it is evident that no patient should consume the plant directly.
The researchers Gastón Soria and Laura Guantay, two of the main authors of the study. (Photo: CyTA-Leloir Agency)
As the researchers indicate, the action of solanocapsin falls within a type of strategy sought by the pharmaceutical industry to develop “selective toxicity” therapies, that is, directed towards specific genetic mutations that are expressed only in cancer cells and not are present in healthy ones, which reduces adverse effects. It is known as “synthetic lethality”.
“Synthetic lethality aims to find drugs that take advantage of the genetic changes of the tumor as an Achilles heel”, summarized the doctor in Chemistry Vanesa Gottifredi, head of the Cell Cycle and Genomic Stability Laboratory of the Leloir Institute Foundation (FIL) and another co-author of the job. She works on the principle that while healthy cells may have genes that don’t do their job properly, they generally don’t suffer pathological consequences because their job tends to be offset by others, she explained.
However, when a combination of deficiencies occurs where a function is lost and also the compensatory or substitute function, then the cell dies. In other words, there may be two genetic anomalies that, when they occur 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. To the patient who has gene 1, the drug does nothing, but to the tumor that developed due to the loss of that gene 1, the drug kills it,” Gottifredi explained.
“Already in its native format, solanocapsin showed increased toxicity on cells deficient in the BRCA2 gene, which made us think about its potential as a precursor structure for a drug, something that had not been proposed until now. That selective toxicity was exactly what we were looking for,” Soria described. “So we developed semisynthetic derivatives and focused on finding their possible molecular target in tumor cells, assuming that we could thus open up new therapeutic opportunities for patients,” she added.
A later stage of that work was done with Cellzome, a German lab owned by GlaxoSmithKline (GSK), the multinational British pharmaceutical company that largely funded this breakthrough through its Trust in Science program. With them, different investigations were carried out aimed at discovering which proteins solanocapsin was bound to within cells and, consequently, detecting those possibly responsible for the selective toxicity action that had been observed. “The five most active proteins were identified and our attention was drawn to the fact that solanocapsin bound with high affinity to the dCK enzyme, which made us think that it could be inhibiting it,” Soria said.
As there were no commercial inhibitors of this enzyme to validate the hypothesis, Soria contacted Caius Radu, a researcher at the University of California in Los Angeles (UCLA), United States, who led the only group in the world that up to that time had developed an inhibitor for dCK, at that time in the experimental stage in vitro. “His participation in this work was key 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 to demonstrate, among other things, that the mechanism of action of solanocapsin is substantially different from that of PARP inhibitors, the current standard therapy.”
Asked about the consequences of the finding, the researcher was enthusiastic: “The possibilities for the future are many. On the one hand, he said, there is the possibility of evaluating dCK inhibition directly on patient samples. On the other hand, now the pharmaceutical industry has compelling evidence to invest in the design of more potent and safer dCK inhibitors with clinical potential”. (Source: CyTA-Leloir Agency)