Scientists from South Ural State University, jointly with their colleagues from Russia, India, Croatia, and Saudi Arabia, have developed and tested new platinum compounds helping effectively fight breast cancer. The research results have been published in the Biomedical Materials & Devices international scientific journal.
Breast cancer is the most widely spread oncological pathology in the world. Despite successful treatment, many patients go through recurrences or suffer from side effects caused by chemotherapy. The new platinum compounds could be used as a base for the creation of safer and more effective medicines.
“For the first time, we have obtained the compounds that not just inhibit the tumour growth, but also protect the body against toxic effects. This opens up new horizons in cancer chemotherapy,” note the research authors.
The scientists focused on AV1 compound, an ionic complex of platinum(IV) consisting of tris(hydroxymethyl)ammonium cations and hexachloroplatinate anions. Tests on MCF-7 breast-cancer cell cultures showed that AV1 is twice more effective for inhibiting the growth of cancer cells than the widely used dasatinib: the IC50 indicator equalled 10.3 µg/ml versus 20.8 µg/ml in case of the standard medicine.
Unlike the classical platinum-drugs (for instance, cisplatin) used for chemotherapy, that often cause severe side effects and lead to tumour’s resistance to therapy, platinum(IV) has an octahedral structure. This allows scientists to create “prodrugs”: compounds that stay stable in bloodstream and become active directly inside a cancer cell.
“Tetrahedral cations and octahedral anions in the AV1 structure ensure not only the high stability, but also the high crystal density. And that’s probably what explains the compound’s low toxicity for healthy tissues,” comments Research Fellow at the SUSU Research Institute for Non-conventional Materials and Resource-Saving Technologies Alena Zykova.
The critical stage was the research conducted in vivo in rats with DMBA-carcinogen-induced breast cancer. The animals treated with AV1 at a dose of 15 mg/kg demonstrated:
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Recovery of mitochondrial functions (ICDH, SDH, and MDH enzymes returned to the indicators of a healthy reference group).
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Strong antioxidant effect: decrease in the oxidative stress level (TBARS) and normalization of the functioning of protective enzymes (SOD, catalase, glutathione).
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Anti-inflammatory effect: inhibiting of the key proinflammatory cytokines (TNF-α, IL-1β, IL-6), which contribute to the growth and metastatic spread of tumour.
It is important to note that even in case of the long-term use this compound did not cause systemic toxicity: no hepatic, nephric, or cardiac pathologies were detected in the test animals, and their body weight remained normal.
Using methods of quantum chemistry (DFT) and QSAR modelling, the scientists found that AV1 interacts with the cell’s DNA in a different way, as compared to its analogues. The compound’s probable key target is topoisomerase I, an enzyme, which is crucial for cancer cells’ reproduction. Blocking of this protein launches a programmed tumour death.
“With the help of quantum chemistry, we model the structure, electron distribution and reacting capacity of the compound. We also use QSAR models: based on big data and machine learning, these analyse how chemical structure is related to biological activity,” shares Research Fellow at the Centre for Informatics and Computing of the Ruđer Bošković Institute, Doctor of Sciences Jurica Novak. “In layman's terms, a computer helps us predict how a substance would behave in a body: whether it could bind to a target protein, and how active or how safe it would be. QSAR is based on a simple idea: similar molecules usually have similar properties. If we know the behaviour of the already studied compounds, with a high degree of probability we can predict the effects of the new ones, which have not been studied yet. Such approaches are crucial for the creation of medicines: those allow to quickly discard the unsuitable options, reduce the number of laboratory experiments, and thus, make the search for new medicines faster and cheaper.”
It is interesting to note that AV2 and AV3 compounds, obtained using the same synthesis method but different organic cations, target progesterone receptors. However, their effectiveness turned out to be significantly lower.
“Synthesis and characterization of the new platinum(IV) compounds opens up new possibilities in chemotherapy. AV1 showed an outstanding safety and effectiveness profile. In the future, additional research is required in order to fully explain the action mechanisms. But already now it becomes clear that this is an extremely promising field of study,” the authors summarize.
This development could become a breakthrough for treatment of chemo-resistant forms of breast cancer, and in particular of triple-negative cancer, when standard approaches often do not work.
The scientists plan on continuing to study the AV1action mechanism and to conduct additional toxicity testing. In case of success, this development could be used as a base for the creation of a Russian next-generation anticancer medicinal product.