Pentamethinium salts suppress key metastatic processes by regulating mitochondrial function and inhibiting dihydroorotate dehydrogenase respiration

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Authors

LEISCHNER FIALOVÁ Jindřiška PETRLÁKOVÁ Kateřina RAUDENSKÁ Martina MIKSATKOVA Lucie ZOBALOVA Renata NAVRÁTIL Jiří ŠMIGOVÁ Jana MOTURU Taraka Ramji VIČAR Tomáš BALVAN Jan VESELA Katerina ABRAMENKO Nikita KEJIK Zdenek KAPLANEK Robert GUMULEC Jaromír ROSEL Daniel MARTASEK Pavel BRÁBEK Jan JAKUBEK Milan NEUZIL Jiri MASAŘÍK Michal

Year of publication 2022
Type Article in Periodical
Magazine / Source Biomedicine & Pharmacotherapy
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.sciencedirect.com/science/article/pii/S0753332222009714
Doi http://dx.doi.org/10.1016/j.biopha.2022.113582
Keywords Dihydroorotate dehydrogenase; Metastasis; Mitochondria; Migration; Pentamethinium salts
Attached files
Description 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.
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