PMID- 31466233
OWN - NLM
STAT- MEDLINE
DCOM- 20200120
LR  - 20211204
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 20
IP  - 17
DP  - 2019 Aug 28
TI  - A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through 
      Mitochondrial Disintegration and Metabolic Collapse.
LID - 10.3390/ijms20174208 [doi]
LID - 4208
AB  - 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.
FAU - Krejcir, Radovan
AU  - Krejcir R
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic.
FAU - Krcova, Lucie
AU  - Krcova L
AUID- ORCID: 0000-0003-2984-3565
AD  - Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, 
      Charles University in Prague, Katerinska 32, 121 08 Prague 2, Czech Republic.
AD  - Department of Analytical Chemistry, University of Chemistry and Technology 
      Prague, Technicka 5, 166 28 Prague 6, Czech Republic.
FAU - Zatloukalova, Pavlina
AU  - Zatloukalova P
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic.
FAU - Briza, Tomas
AU  - Briza T
AD  - Department of Analytical Chemistry, University of Chemistry and Technology 
      Prague, Technicka 5, 166 28 Prague 6, Czech Republic.
AD  - BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, 252 50 
      Vestec, Czech Republic.
FAU - Coates, Philip J
AU  - Coates PJ
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic.
FAU - Sterba, Martin
AU  - Sterba M
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic.
FAU - Muller, Petr
AU  - Muller P
AUID- ORCID: 0000-0002-8404-4494
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic.
FAU - Kralova, Jarmila
AU  - Kralova J
AD  - Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, 
      Charles University in Prague, Katerinska 32, 121 08 Prague 2, Czech Republic.
FAU - Martasek, Pavel
AU  - Martasek P
AD  - Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, 
      Charles University in Prague, Katerinska 32, 121 08 Prague 2, Czech Republic.
AD  - General University Hospital, U nemocnice 2, 128 08 Prague 2, Czech Republic.
FAU - Kral, Vladimir
AU  - Kral V
AD  - Department of Analytical Chemistry, University of Chemistry and Technology 
      Prague, Technicka 5, 166 28 Prague 6, Czech Republic.
AD  - BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, 252 50 
      Vestec, Czech Republic.
FAU - Vojtesek, Borivoj
AU  - Vojtesek B
AD  - Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer 
      Institute, 656 53 Brno, Czech Republic. vojtesek@mou.cz.
LA  - eng
GR  - 17-07822S/Grantova Agentura Ceske Republiky/
GR  - RVO-VFN 64165/2012/Ministerstvo Zdravotnictvi Ceske Republiky/
GR  - NPS I - LO1413, NPS II - LQ1604/Ministerstvo Skolstvi, Mladeze a Telovychovy/
GR  - LM2015062, LM2015064/EATRIS-CZ/
PT  - Journal Article
DEP - 20190828
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Carbocyanines)
RN  - 0 (Quaternary Ammonium Compounds)
RN  - 0 (Quinazolines)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Antineoplastic Agents/chemistry/*pharmacology
MH  - Carbocyanines/chemistry
MH  - Cell Line, Tumor
MH  - Humans
MH  - Mitochondria/*drug effects/metabolism
MH  - *Mitophagy
MH  - Protein Kinases/metabolism
MH  - Quaternary Ammonium Compounds/chemistry/*pharmacology
MH  - Quinazolines/chemistry/*pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
PMC - PMC6747461
OTO - NOTNLM
OT  - autophagy
OT  - cancer therapy
OT  - glucose metabolism
OT  - mitochondria
COIS- The authors declare no conflict of interest.
EDAT- 2019/08/31 06:00
MHDA- 2020/01/21 06:00
PMCR- 2019/09/01
CRDT- 2019/08/31 06:00
PHST- 2019/07/12 00:00 [received]
PHST- 2019/08/22 00:00 [revised]
PHST- 2019/08/23 00:00 [accepted]
PHST- 2019/08/31 06:00 [entrez]
PHST- 2019/08/31 06:00 [pubmed]
PHST- 2020/01/21 06:00 [medline]
PHST- 2019/09/01 00:00 [pmc-release]
AID - ijms20174208 [pii]
AID - ijms-20-04208 [pii]
AID - 10.3390/ijms20174208 [doi]
PST - epublish
SO  - Int J Mol Sci. 2019 Aug 28;20(17):4208. doi: 10.3390/ijms20174208.