Dissertation study on the effects of selenium-containing compounds on cancer metabolism
Low therapeutic efficacy and resistance to conventional drugs remain the major obstacles in modern chemotherapy. Scientists around the world are therefore constantly searching for new drugs with different modes of action that, alone or in combination with other drugs, can help cancer patients. In recent years, selenium-containing compounds have been extensively studied as anticancer agents due to the characteristic properties of selenium.
The aim of this thesis was to evaluate the chemotherapeutic potential of isoselenazolium salts, a novel class of organoselenium compounds, and to explore their mechanism of action.
Unlike normal cells, cancer cells divide and grow rapidly. To support the growth, cancer cells require a large amount of energy and, the ways of producing energy are different from normal cells. Pyruvate kinase M2 (PKM2) is a cancer cell-specific enzyme that regulates the course of glucose metabolism, mitochondrial functions and promotes cancer development.
In this work, isoselenazole salts were shown to specifically inhibit PKM2 activity and prevent malignant cells from producing energy in the required amount. More extensive research has revealed the molecular mechanism of action of the new compounds. It was demonstrated that isoselenazolium salts inhibit PKM2 in an unusual way by inducing the formation of inactive PKM2 tetrameters. In addition, these types of compounds were shown to suppress respiration of cancer cells and cause significant oxidative stress.
Image from Pāvels Dimitrijevs' dissertation thesis
The findings establish a ground for the novel class of drug candidates with a unique molecular mechanism and reveal specific structural features of PKM2 that will be an integral part of future studies focusing on the metabolic role of PKM2 in cancer.
Pāvels Dimitrijevs will defend his thesis "Targeting cancer metabolism with isoselenazolium salts" on 15 January 2024 Read more
