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Open AccessArticle

A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse

1
Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic
2
Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Kateřinská 32, 121 08 Prague 2, Czech Republic
3
Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic
4
BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic
5
General University Hospital, U nemocnice 2, 128 08 Prague 2, Czech Republic
*
Author to whom correspondence should be addressed.
There authors contributed equally to this work.
Deceased at 17 April 2019.
Int. J. Mol. Sci. 2019, 20(17), 4208; https://doi.org/10.3390/ijms20174208
Received: 12 July 2019 / Revised: 22 August 2019 / Accepted: 23 August 2019 / Published: 28 August 2019
(This article belongs to the Section Molecular Oncology)
Cancer cells preferentially utilize glycolysis for ATP production even in aerobic conditions (the Warburg effect) and adapt mitochondrial processes to their specific needs. Recent studies indicate that altered mitochondrial activities in cancer represent an actionable target for therapy. We previously showed that salt 1-3C, a quinoxaline unit (with cytotoxic activity) incorporated into a meso-substituted pentamethinium salt (with mitochondrial selectivity and fluorescence properties), displayed potent cytotoxic effects in vitro and in vivo, without significant toxic effects to normal tissues. Here, we investigated the cytotoxic mechanism of salt 1-3C compared to its analogue, salt 1-8C, with an extended side carbon chain. Live cell imaging demonstrated that salt 1-3C, but not 1-8C, is rapidly incorporated into mitochondria, correlating with increased cytotoxicity of salt 1-3C. The accumulation in mitochondria led to their fragmentation and loss of function, accompanied by increased autophagy/mitophagy. Salt 1-3C preferentially activated AMP-activated kinase and inhibited mammalian target of rapamycin (mTOR) signaling pathways, sensors of cellular metabolism, but did not induce apoptosis. These data indicate that salt 1-3C cytotoxicity involves mitochondrial perturbation and disintegration, and such compounds are promising candidates for targeting mitochondria as a weak spot of cancer. View Full-Text
Keywords: cancer therapy; glucose metabolism; mitochondria; autophagy cancer therapy; glucose metabolism; mitochondria; autophagy
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Krejcir, R.; Krcova, L.; Zatloukalova, P.; Briza, T.; Coates, P.J.; Sterba, M.; Muller, P.; Kralova, J.; Martasek, P.; Kral, V.; Vojtesek, B. A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse. Int. J. Mol. Sci. 2019, 20, 4208.

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