The researchers from the Medical University of Bialystok (Anna Szymanowska, Dominika Radomska, Robert Czarnomysy, Krzysztof Bielawski, Anna Bielawska) published the article „The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures” in Journal of Enzyme Inhibition and Medicinal Chemistry.
Breast cancer is the most frequently diagnosed and second most lethal cancer in the world. Although this disease is curable in about 70-80% of patients in its early stages, in many cases it is diagnosed too late. The worse prognosis and the effectiveness of therapy are also influenced by the fact that this cancer metastasizes quite quickly and becomes resistant to standard cytostatic treatment. Therefore, it is necessary to constantly search for and create new drugs with high anticancer activity.
Our studies have shown that new derivatives of the fused tricyclic system of triazine, pyrazole and tetrazole with a sulfonamide moiety are characterized by high anticancer potential in breast cancer. In vitro observations clearly showed that these derivatives may be more effective than previously used preparations, including the reference drug — cisplatin. They statistically significantly reduce the viability of two tested breast cancer cell lines: MCF-7 and MDA-MB-231. Importantly, towards normal human MCF-10A breast epithelial cells, the new derivatives show lower cytotoxicity than towards the tested cancer cells, suggesting their greater selectivity and, therefore, potential therapeutic benefits. It is also important that these compounds exhibit high cytotoxic activity at the nanomolar level. They induce apoptosis by activating the extrinsic and intrinsic pathways, and increase the activity of p53, Bax and ROS and reduce the level of NF-κB, which play a key role in activating this process. Moreover, the new derivatives also reduce the level of mTOR, which plays a major role in the autophagy process.
The obtained results expand the current knowledge about the molecular mechanism of anticancer action of tricyclic sulfonamide derivatives. Additionally, these studies identify a possible mechanism for the anticancer activity of this group of compounds.
The research was partly financed by research projects: Medical University of Bialystok (B.SUB.23.408), Siedlce University of Natural Sciences and Humanities (UPH/WNSP/ICH/zadaniebadawcze/143/23/B), and Medical University of Lublin (DS 730). A.S. is supported by Polish National Agency for Academic Exchange (NAWA) within the Bekker Programme (BPN/BEK/2021/1/00115).
Link to the article: The activity of pyrazolo[4,3-e][1,2,4]triazine and pyrazolo[4,3-e]tetrazolo[1,5-b][1,2,4]triazine sulphonamide derivatives in monolayer and spheroid breast cancer cell cultures
