-
Something wrong with this record ?
Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings
O. Lenčová-Popelová, H. Jansová, E. Jirkovský, J. Bureš, A. Jirkovská-Vávrová, Y. Mazurová, P. Reimerová, L. Vostatková, M. Adamcová, M. Hroch, Z. Pokorná, P. Kovaříková, T. Šimůnek, M. Štěrba,
Language English Country Ireland
Document type Journal Article
Grant support
NT13457
MZ0
CEP Register
- MeSH
- Anthracyclines toxicity MeSH
- Chronic Disease MeSH
- Daunorubicin toxicity MeSH
- Nitric Oxide Donors pharmacology MeSH
- Doxorubicin toxicity MeSH
- Cardiotonic Agents pharmacology MeSH
- Cardiotoxicity MeSH
- Rabbits MeSH
- Molsidomine pharmacology MeSH
- Cell Line, Tumor MeSH
- Heart Diseases chemically induced prevention & control MeSH
- Oxidative Stress drug effects MeSH
- Lipid Peroxidation drug effects MeSH
- Cell Proliferation drug effects MeSH
- Antibiotics, Antineoplastic toxicity MeSH
- Reactive Oxygen Species metabolism MeSH
- Ventricular Remodeling drug effects MeSH
- Heart Failure prevention & control MeSH
- Animals MeSH
- Check Tag
- Rabbits MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.
References provided by Crossref.org
- 000
- 00000naa a2200000 a 4500
- 001
- bmc17023524
- 003
- CZ-PrNML
- 005
- 20181212104612.0
- 007
- ta
- 008
- 170720s2016 ie f 000 0|eng||
- 009
- AR
- 024 7_
- $a 10.1016/j.tox.2016.11.002 $2 doi
- 035 __
- $a (PubMed)27816693
- 040 __
- $a ABA008 $b cze $d ABA008 $e AACR2
- 041 0_
- $a eng
- 044 __
- $a ie
- 100 1_
- $a Lenčová-Popelová, Olga $u Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 _BN001885
- 245 10
- $a Are cardioprotective effects of NO-releasing drug molsidomine translatable to chronic anthracycline cardiotoxicity settings / $c O. Lenčová-Popelová, H. Jansová, E. Jirkovský, J. Bureš, A. Jirkovská-Vávrová, Y. Mazurová, P. Reimerová, L. Vostatková, M. Adamcová, M. Hroch, Z. Pokorná, P. Kovaříková, T. Šimůnek, M. Štěrba,
- 520 9_
- $a Chronic anthracycline (ANT) cardiotoxicity is a serious complication of cancer chemotherapy. Molsidomine, a NO-releasing drug, has been found cardioprotective in different models of I/R injury and recently in acute high-dose ANT cardiotoxicity. Hence, we examined whether its cardioprotective effects are translatable to chronic ANT cardiotoxicity settings without induction of nitrosative stress and interference with antiproliferative action of ANTs. The effects of molsidomine (0.025 and 0.5mg/kg, i.v.) were studied on the well-established model of chronic ANT cardiotoxicity in rabbits (daunorubicin/DAU/3mg/kg/week for 10 weeks). Molsidomine was unable to significantly attenuate mortality, development of heart failure and morphological damage induced by DAU. Molsidomine did not alter DAU-induced myocardial lipoperoxidation, MnSOD down-regulation, up-regulation of HO-1, IL-6, and molecular markers of cardiac remodeling. Although molsidomine increased 3-nitrotyrosine in the myocardium, this event had no impact on cardiotoxicity development. Using H9c2 myoblasts and isolated cardiomyocytes, it was found that SIN-1 (an active metabolite of molsidomine) induces significant protection against ANT toxicity, but only at high concentrations. In leukemic HL-60 cells, SIN-1 initially augmented ANT cytotoxicity (in low and clinically achievable concentrations), but it protected these cells against ANT in the high concentrations. UHPLC-MS/MS investigation demonstrated that the loss of ANT cytotoxicity after co-incubation of the cells in vitro with high concentrations of SIN-1 is caused by unexpected chemical depletion of DAU molecule. The present study demonstrates that cardioprotective effects of molsidomine are not translatable to clinically relevant chronic form of ANT cardiotoxicity. The augmentation of antineoplastic effects of ANT in low (nM) concentrations may deserve further study.
- 650 _2
- $a zvířata $7 D000818
- 650 _2
- $a antracykliny $x toxicita $7 D018943
- 650 _2
- $a protinádorová antibiotika $x toxicita $7 D000903
- 650 _2
- $a kardiotonika $x farmakologie $7 D002316
- 650 _2
- $a kardiotoxicita $7 D066126
- 650 _2
- $a nádorové buněčné linie $7 D045744
- 650 _2
- $a proliferace buněk $x účinky léků $7 D049109
- 650 _2
- $a chronická nemoc $7 D002908
- 650 _2
- $a daunomycin $x toxicita $7 D003630
- 650 _2
- $a doxorubicin $x toxicita $7 D004317
- 650 _2
- $a nemoci srdce $x chemicky indukované $x prevence a kontrola $7 D006331
- 650 _2
- $a srdeční selhání $x prevence a kontrola $7 D006333
- 650 _2
- $a peroxidace lipidů $x účinky léků $7 D015227
- 650 _2
- $a molsidomin $x farmakologie $7 D008981
- 650 _2
- $a donory oxidu dusnatého $x farmakologie $7 D020030
- 650 _2
- $a oxidační stres $x účinky léků $7 D018384
- 650 _2
- $a králíci $7 D011817
- 650 _2
- $a reaktivní formy kyslíku $x metabolismus $7 D017382
- 650 _2
- $a remodelace komor $x účinky léků $7 D020257
- 655 _2
- $a časopisecké články $7 D016428
- 700 1_
- $a Jansová, Hana. $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 xx0230344
- 700 1_
- $a Jirkovský, Eduard $u Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 uk20201094982
- 700 1_
- $a Bureš, Jan. $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 xx0230346
- 700 1_
- $a Vávrová, Anna $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 _AN050099
- 700 1_
- $a Mazurová, Yvona $u Department of Histology and Embryology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
- 700 1_
- $a Reimerová, Petra $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
- 700 1_
- $a Vostatková, Lucie $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 xx0230338
- 700 1_
- $a Adamcová, Michaela $u Department of Physiology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 gn_A_00001181
- 700 1_
- $a Hroch, Miloš, $d 1976- $7 xx0076212 $u Department of Medical Biochemistry, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
- 700 1_
- $a Pokorná, Zuzana $u Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic.
- 700 1_
- $a Štěrbová-Kovaříková, Petra $u Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 mzk2007411146
- 700 1_
- $a Šimůnek, Tomáš $u Department of Biochemical Sciences, Faculty of Pharmacy in Hradec Králové, Charles University, Hradec Králové, Czech Republic. $7 xx0019029
- 700 1_
- $a Štěrba, Martin $u Department of Pharmacology, Faculty of Medicine in Hradec Králové, Charles University, Hradec Králové, Czech Republic. Electronic address: sterbam@lfhk.cuni.cz. $7 xx0076492
- 773 0_
- $w MED00004533 $t Toxicology $x 1879-3185 $g Roč. 372, č. - (2016), s. 52-63
- 856 41
- $u https://pubmed.ncbi.nlm.nih.gov/27816693 $y Pubmed
- 910 __
- $a ABA008 $b sig $c sign $y a $z 0
- 990 __
- $a 20170720 $b ABA008
- 991 __
- $a 20181212104736 $b ABA008
- 999 __
- $a ok $b bmc $g 1239205 $s 984437
- BAS __
- $a 3
- BAS __
- $a PreBMC
- BMC __
- $a 2016 $b 372 $c - $d 52-63 $e 20161102 $i 1879-3185 $m Toxicology $n Toxicology $x MED00004533
- GRA __
- $a NT13457 $p MZ0
- LZP __
- $a Pubmed-20170720
