Biomedicine & Pharmacotherapy (Oct 2022)
Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration
- Jindriska Leischner Fialova,
- Katerina Hönigova,
- Martina Raudenska,
- Lucie Miksatkova,
- Renata Zobalova,
- Jiri Navratil,
- Jana Šmigová,
- Taraka Ramji Moturu,
- Tomas Vicar,
- Jan Balvan,
- Katerina Vesela,
- Nikita Abramenko,
- Zdenek Kejik,
- Robert Kaplanek,
- Jaromir Gumulec,
- Daniel Rosel,
- Pavel Martasek,
- Jan Brábek,
- Milan Jakubek,
- Jiri Neuzil,
- Michal Masarik
Affiliations
- Jindriska Leischner Fialova
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Katerina Hönigova
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Martina Raudenska
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic
- Lucie Miksatkova
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Renata Zobalova
- Institute of Biotechnology, Czech Academy of Sciences, Prumyslova 595, CZ-252 50 Vestec, Czech Republic
- Jiri Navratil
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Jana Šmigová
- Department of Cell Biology, Charles University, Viničná 7, 128 44 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 252 42 Vestec u Prahy, Czech Republic
- Taraka Ramji Moturu
- Crop Production and Biostimulation Laboratory, Interfacultary School of Bioengineers, Université libre de Bruxelles, Belgium
- Tomas Vicar
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Jan Balvan
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Katerina Vesela
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Nikita Abramenko
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Zdenek Kejik
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Robert Kaplanek
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Jaromir Gumulec
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic
- Daniel Rosel
- Department of Cell Biology, Charles University, Viničná 7, 128 44 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 252 42 Vestec u Prahy, Czech Republic
- Pavel Martasek
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic
- Jan Brábek
- Department of Cell Biology, Charles University, Viničná 7, 128 44 Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 252 42 Vestec u Prahy, Czech Republic
- Milan Jakubek
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic; Corresponding author at: BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic.
- Jiri Neuzil
- Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital in Prague, Ke Karlovu 455, 120 00 Prague, Czech Republic; Institute of Biotechnology, Czech Academy of Sciences, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; School of Pharmacy and Medical Science, Griffith University, Parklands Avenue, Southport 4222 QLD, Australia; Faculty of Science, Charles University, Vinicna 7, Prague 128 44, Czech Republic; Corresponding author at: Institute of Biotechnology, Czech Academy of Sciences, Prumyslova 595, CZ-252 50 Vestec, Czech Republic.
- Michal Masarik
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic; BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, CZ-252 50 Vestec, Czech Republic; Correspondence to: Department of Physiology and Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00 Brno, Czech Republic.
- Journal volume & issue
-
Vol. 154
p. 113582
Abstract
Mitochondria generate energy and building blocks required for cellular growth and function. The notion that mitochondria are not involved in the cancer growth has been challenged in recent years together with the emerging idea of mitochondria as a promising therapeutic target for oncologic diseases. Pentamethinium salts, cyan dyes with positively charged nitrogen on the benzothiazole or indole part of the molecule, were originally designed as mitochondrial probes. In this study, we show that pentamethinium salts have a strong effect on mitochondria, suppressing cancer cell proliferation and migration. This is likely linked to the strong inhibitory effect of the salts on dihydroorotate dehydrogenase (DHODH)-dependent respiration that has a key role in the de novo pyrimidine synthesis pathway. We also show that pentamethinium salts cause oxidative stress, redistribution of mitochondria, and a decrease in mitochondria mass. In conclusion, pentamethinium salts present novel anti-cancer agents worthy of further studies.