Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

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,

. 2019 ; 20 (17) : . [pub] 20190828

Jazyk angličtina Země Švýcarsko

Typ dokumentu časopisecké články

Perzistentní odkaz   https://www.medvik.cz/link/bmc20005971

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

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

000      
00000naa a2200000 a 4500
001      
bmc20005971
003      
CZ-PrNML
005      
20200518132228.0
007      
ta
008      
200511s2019 sz f 000 0|eng||
009      
AR
024    7_
$a 10.3390/ijms20174208 $2 doi
035    __
$a (PubMed)31466233
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a sz
100    1_
$a Krejcir, Radovan $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
245    12
$a A Cyclic Pentamethinium Salt Induces Cancer Cell Cytotoxicity through Mitochondrial Disintegration and Metabolic Collapse / $c R. Krejcir, L. Krcova, P. Zatloukalova, T. Briza, PJ. Coates, M. Sterba, P. Muller, J. Kralova, P. Martasek, V. Kral, B. Vojtesek,
520    9_
$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.
650    _2
$a protinádorové látky $x chemie $x farmakologie $7 D000970
650    _2
$a karbocyaniny $x chemie $7 D002232
650    _2
$a nádorové buněčné linie $7 D045744
650    _2
$a lidé $7 D006801
650    _2
$a mitochondrie $x účinky léků $x metabolismus $7 D008928
650    12
$a mitofagie $7 D063306
650    _2
$a proteinkinasy $x metabolismus $7 D011494
650    _2
$a kvartérní amoniové sloučeniny $x chemie $x farmakologie $7 D000644
650    _2
$a chinazoliny $x chemie $x farmakologie $7 D011799
650    _2
$a TOR serin-threoninkinasy $x metabolismus $7 D058570
655    _2
$a časopisecké články $7 D016428
700    1_
$a Krcova, Lucie $u Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Kateřinská 32, 121 08 Prague 2, Czech Republic. Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic.
700    1_
$a Zatloukalova, Pavlina $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
700    1_
$a Briza, Tomas $u Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic. BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic.
700    1_
$a Coates, Philip J $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
700    1_
$a Sterba, Martin $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
700    1_
$a Muller, Petr $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic.
700    1_
$a Kralova, Jarmila $u Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Kateřinská 32, 121 08 Prague 2, Czech Republic.
700    1_
$a Martasek, Pavel $u Department of Pediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University in Prague, Kateřinská 32, 121 08 Prague 2, Czech Republic. General University Hospital, U nemocnice 2, 128 08 Prague 2, Czech Republic.
700    1_
$a Kral, Vladimir $u Department of Analytical Chemistry, University of Chemistry and Technology Prague, Technická 5, 166 28 Prague 6, Czech Republic. BIOCEV, First Faculty of Medicine, Charles University, Průmyslová 595, 252 50 Vestec, Czech Republic.
700    1_
$a Vojtesek, Borivoj $u Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, 656 53 Brno, Czech Republic. vojtesek@mou.cz.
773    0_
$w MED00176142 $t International journal of molecular sciences $x 1422-0067 $g Roč. 20, č. 17 (2019)
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31466233 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20200511 $b ABA008
991    __
$a 20200518132228 $b ABA008
999    __
$a ok $b bmc $g 1524829 $s 1096027
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 20 $c 17 $e 20190828 $i 1422-0067 $m International journal of molecular sciences $n Int J Mol Sci $x MED00176142
GRA    __
$a 17-07822S $p Grantová Agentura České Republiky
GRA    __
$a RVO-VFN 64165/2012 $p Ministerstvo Zdravotnictví Ceské Republiky
GRA    __
$a NPS I - LO1413, NPS II - LQ1604 $p Ministerstvo Školství, Mládeže a Tělovýchovy
GRA    __
$a LM2015062, LM2015064 $p EATRIS-CZ
LZP    __
$a Pubmed-20200511

Najít záznam

Citační ukazatele

Možnosti archivace