A multidisciplinary team from the Rey Juan Carlos University and the Carlos III Health Institute has developed two new antitumor compounds that contain platinum. The results of the trials have shown that these compounds would have greater potency and fewer side effects for the patient.

Currently, three drugs containing the platinum element are used in chemotherapy worldwide (cisplatin, carboplatin and oxaliplatin) against various types of tumors. However, these treatments generate severe side effects in the patient such as balance or hearing problems, kidney and liver toxicity, hair loss, anemia and resistance in advanced stages. Furthermore, these platinum compounds are quickly inactivated by various molecules in the body - only a small amount of the drug manages to reach the cell intact - and attack the cellular DNA, causing damage to its structure and leading to cell death.

In the work developed by Chemical and Environmental Engineering Group (GIQA) and the Molecular Diabecancer Group of the Rey Juan Carlos University (URJC), together with the Endocrine Tumor Unit of the Carlos III Health Institute, two new platinum antitumor compounds have been generated with the aim of overcoming all these limitations. By introducing modifications in their molecular structure, these new drugs are less reactive against inactivation, more stable and allow greater accumulation inside the cell.

“These compounds have been designed so that, once they have arrived intact inside the cell, they are transformed into a biologically active species of platinum that attacks DNA. Furthermore, they contain two additional molecules in their structure with silicon atoms, also with anti-cancer properties, and which are released into the cellular environment, thus generating a drug with enhanced activity,” highlights Rafael García Muñoz, researcher in the GIQA group and main co-author. of the published study in the Journal of Medicinal Chemistry.

Laboratory trials for the treatment of intestinal tumors

The research team has carried out an analysis of the anticancer activity in colon tumor cells and has observed that one of the two drugs (called Pt(IV)-biSi-2) is capable of killing more cells at very low concentrations. , showing greater activity and selectivity in vitro between cancer cells and healthy intestinal cells. “This result is very promising. The evaluation of the activity of this compound in mice with colon tumors, used at a very low dose, has managed to reduce the size of the tumors to a greater extent than cisplatin and with minimal side effects, reducing kidney and liver toxicity," he points out. Francisco Navas, first co-author of the study and researcher of the GIQA group.

The study of the mechanism of action has shown that both compounds follow a cell death activation pathway independent of the tumor suppressor protein, the so-called p53 or the “guardian of the genome.” This molecule is responsible for activating various pathways that cause the death of tumor cells treated with cisplatin. However, many cancer cells have mutations in p53, leading to resistance to these treatments. “The fact that the new compounds follow a route independent of this protein is potentially interesting to overcome drug resistance,” says Rafael García. “We have shown that this new compound is transformed inside the cell very quickly to an active platinum species, which could be directly related to the good results obtained,” he concludes.

Furthermore, the platinum drugs generated in this work offer the possibility of being incorporated into nanoparticles thanks to the additional molecules in their structure. These small vehicles (a nanometer is one billionth of a meter) would allow a more efficient and prolonged release of the drug at the tumor site, as well as greater assimilation and compatibility in the body.

Irene Vega

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