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A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse
R. Krejcir, L. Krcova, P. Zatloukalova, T. Briza, PJ. Coates, M. Sterba, P. Muller, J. Kralova, P. Martasek, V. Kral, B. Vojtesek,
Jazyk angličtina Země Švýcarsko
Typ dokumentu časopisecké články
Grantová podpora
17-07822S
Grantová Agentura České Republiky
RVO-VFN 64165/2012
Ministerstvo Zdravotnictví Ceské Republiky
NPS I - LO1413, NPS II - LQ1604
Ministerstvo Školství, Mládeže a Tělovýchovy
LM2015062, LM2015064
EATRIS-CZ
NLK
Free Medical Journals
od 2000
Freely Accessible Science Journals
od 2000
PubMed Central
od 2007
Europe PubMed Central
od 2007
ProQuest Central
od 2000-03-01
Open Access Digital Library
od 2000-01-01
Open Access Digital Library
od 2007-01-01
Health & Medicine (ProQuest)
od 2000-03-01
ROAD: Directory of Open Access Scholarly Resources
od 2000
PubMed
31466233
DOI
10.3390/ijms20174208
Knihovny.cz E-zdroje
- MeSH
- chinazoliny chemie farmakologie MeSH
- karbocyaniny chemie MeSH
- kvartérní amoniové sloučeniny chemie farmakologie MeSH
- lidé MeSH
- mitochondrie účinky léků metabolismus MeSH
- mitofagie * MeSH
- nádorové buněčné linie MeSH
- proteinkinasy metabolismus MeSH
- protinádorové látky chemie farmakologie MeSH
- TOR serin-threoninkinasy metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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.
Citace poskytuje Crossref.org
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- $a 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.
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