Makrecka-Kuka 2020 Sci Rep

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Makrecka-Kuka M, Dimitrijevs P, Domracheva I, Jaudzems K, Dambrova M, Arsenyan P (2020) Fused isoselenazolium salts suppress breast cancer cell growth by dramatic increase in pyruvate-dependent mitochondrial ROS production. Sci Rep 10:21595.

» PMID: 33299068 Open Access

Makrecka-Kuka Marina, Dimitrijevs Pavels, Domracheva Ilona, Jaudzems Kristaps, Dambrova Maija, Arsenyan Pavel (2020) Sci Rep

Abstract: The development of targeted drugs for the treatment of cancer remains an unmet medical need. This study was designed to investigate the mechanism underlying breast cancer cell growth suppression caused by fused isoselenazolium salts. The ability to suppress the proliferation of malignant and normal cells in vitro as well as the effect on NAD homeostasis (NAD+, NADH, and NMN levels), NAMPT inhibition and mitochondrial functionality were studied. The interactions of positively charged isoselenazolium salts with the negatively charged mitochondrial membrane model were assessed. Depending on the molecular structure, fused isoselenazolium salts display nanomolar to high micromolar cytotoxicities against MCF-7 and 4T1 breast tumor cell lines. The studied compounds altered NMN, NAD+, and NADH levels and the NAD+/NADH ratio. Mitochondrial functionality experiments showed that fused isoselenazolium salts inhibit pyruvate-dependent respiration but do not directly affect complex I of the electron transfer system. Moreover, the tested compounds induce an immediate dramatic increase in the production of reactive oxygen species. In addition, the isoselenazolothiazolium derivative selectively binds to cardiolipin in a liposomal model. Isoselenazolium salts may be a promising platform for the development of potent drug candidates for anticancer therapy that impact mitochondrial pyruvate-dependent metabolism in breast cancer cells.


Bioblast editor: Plangger M O2k-Network Lab: LV Riga Makrecka-Kuka M


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Permeabilized cells 


Coupling state: LEAK, OXPHOS  Pathway: N, S, NS, ROX  HRR: Oxygraph-2k, O2k-Fluorometer 

2020-12, AmR