Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

Ewa Grabowska; Magdalena Czerniecka; Urszula Czyżewska; Aneta Zambrzycka; Zenon Łotowski; Adam Tylicki

doi:10.1080/14756366.2020.1844681

Differences in the efficiency of 3-deazathiamine and oxythiamine pyrophosphates as inhibitors of pyruvate dehydrogenase complex and growth of HeLa cells in vitro

J Enzyme Inhib Med Chem. 2021 Dec;36(1):122-129. doi: 10.1080/14756366.2020.1844681.

Authors

Ewa Grabowska¹, Magdalena Czerniecka², Urszula Czyżewska², Aneta Zambrzycka³, Zenon Łotowski⁴, Adam Tylicki²

Affiliations

¹ Doctoral School of Exact and Natural Sciences, University of Białystok, Białystok, Poland.
² Department of Microbiology and Biotechnology, University of Białystok, Białystok, Poland.
³ Argenta Sp. z o.o, Poznań, Poland.
⁴ Department of Organic Chemistry, University of Białystok, Białystok, Poland.

Abstract

Oxythiamine (OT) and 3-deazathiamine (DAT) are the antimetabolites of thiamine. The aim of study was to compare the effects of OT and DAT pyrophosphates (-PP) on the kinetics of mammalian pyruvate dehydrogenase complex (PDHC) and the in vitro culture of HeLa cells. The kinetic study showed that 3-deazathiamine pyrophosphate (DATPP) was a much stronger competitive inhibitor (K_i = 0.0026 μM) of PDHC than OTPP (K_i = 0.025 μM). Both K_i values were much lower versus K _m for thiamine pyrophosphate (0.06 μM). However, DATPP added to the culture medium for the HeLa cells culture did not hamper the rate of cell growth and showed not significant impact on the viability of the cells, whereas OTPP and OT showed a significant cytostatic effect. The differences between the thiamine antivitamins in their effect on cell growth in vitro may be due to differences in physicochemical properties and difficulty in DAT transport across the cell membrane.

Keywords: Apoptosis; thiamine antimetabolites; thiamine pyrophosphate-dependent enzyme inhibitors.

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
HeLa Cells
Humans
Molecular Structure
Pyruvate Dehydrogenase Complex / antagonists & inhibitors*
Pyruvate Dehydrogenase Complex / metabolism
Structure-Activity Relationship
Thiamine / analogs & derivatives
Thiamine / chemistry
Thiamine / pharmacology*
Tumor Cells, Cultured

Substances

Antineoplastic Agents
Enzyme Inhibitors
Pyruvate Dehydrogenase Complex
Thiamine

Grants and funding

This study was supported by the Ministry of Science and Higher Education in Poland as a part of subsidies for maintaining the research potential granted to the Faculty of Biology of the University of Białystok (SWB-8) and Faculty of Chemistry of the University of Białystok.