Abstract
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
main aim of this study was to evaluate the chemotherapeutic potential of isoselenazolium salts,
a novel class of organoselenium compounds, and to explore their mechanism of action.
The first series of isoselenazolium salts exhibited selective cytotoxicity against breast
cancer cell lines. These compounds modulated mitochondrial respiration, increased reactive
oxygen species production, altered NAD+
homeostasis, inhibited poly(ADP-ribose) polymerase
1 (PARP1) and possibly interfered with cardiolipin, a signature phospholipid of mitochondria.
To test the latter, a new fluorescent cardiolipin-specific probe and a competitive binding assay
were developed to quantitatively describe the drugs` affinity for cardiolipin. Using a new
method, it was proved that the affinity of isoselenazolium salts for cardiolipin is low, and their
interaction is not related to the pharmacological effect.
The second series of isoselenazolium salts with a modified structure was designed to
have improved PARP1 inhibitory activity. These compounds displayed high cytotoxicity
against T-cell leukaemia, breast, liver, and lung cancer cells. Although the PARP1 inhibitory
activity was improved, detailed studies of the mechanism of action showed that isoselenazolium
salts are potent and selective inhibitors of pyruvate kinase M2 (PKM2), an enzyme, that is
highly expressed in various types of tumours. On the basis of NMR, size-exclusion
chromatography, mass photometry, differential scanning fluorimetry, isothermal titration
calorimetry, and enzyme kinetic data, isoselenazolium salts were found to be competitive
inhibitors and at the same time induce an unstable PKM2 homotetramer formation. Thus,
PKM2 translocation to the nucleus is blocked, preventing its nonmetabolic functions.
The discovery of robust PKM2 inhibitors could serve as the basis for new anticancer
drug candidates and provide an important insight into the fundamental role of PKM2
in oncogenesis.
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
main aim of this study was to evaluate the chemotherapeutic potential of isoselenazolium salts,
a novel class of organoselenium compounds, and to explore their mechanism of action.
The first series of isoselenazolium salts exhibited selective cytotoxicity against breast
cancer cell lines. These compounds modulated mitochondrial respiration, increased reactive
oxygen species production, altered NAD+
homeostasis, inhibited poly(ADP-ribose) polymerase
1 (PARP1) and possibly interfered with cardiolipin, a signature phospholipid of mitochondria.
To test the latter, a new fluorescent cardiolipin-specific probe and a competitive binding assay
were developed to quantitatively describe the drugs` affinity for cardiolipin. Using a new
method, it was proved that the affinity of isoselenazolium salts for cardiolipin is low, and their
interaction is not related to the pharmacological effect.
The second series of isoselenazolium salts with a modified structure was designed to
have improved PARP1 inhibitory activity. These compounds displayed high cytotoxicity
against T-cell leukaemia, breast, liver, and lung cancer cells. Although the PARP1 inhibitory
activity was improved, detailed studies of the mechanism of action showed that isoselenazolium
salts are potent and selective inhibitors of pyruvate kinase M2 (PKM2), an enzyme, that is
highly expressed in various types of tumours. On the basis of NMR, size-exclusion
chromatography, mass photometry, differential scanning fluorimetry, isothermal titration
calorimetry, and enzyme kinetic data, isoselenazolium salts were found to be competitive
inhibitors and at the same time induce an unstable PKM2 homotetramer formation. Thus,
PKM2 translocation to the nucleus is blocked, preventing its nonmetabolic functions.
The discovery of robust PKM2 inhibitors could serve as the basis for new anticancer
drug candidates and provide an important insight into the fundamental role of PKM2
in oncogenesis.
Original language | English |
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Qualification | Doctor of Science |
Awarding Institution |
|
Supervisors/Advisors |
|
Award date | 15 Jan 2024 |
Place of Publication | Riga |
Publisher | |
DOIs | |
Publication status | Published - 2024 |
Externally published | Yes |
Keywords*
- Doctoral Thesis
- cancer
- cardiolipin
- isoselenazolium salts
- metabolic reprogramming
- PARP1
- pyruvate kinase M2
- selenium
Field of Science*
- 1.4 Chemical sciences
- 3.2 Clinical medicine
- 3.1 Basic medicine
Publication Type*
- 4. Doctoral Thesis