Q59690810
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Salicylaldehyde isonicotinoyl hydrazone (SIH) is a lipophilic, orally-active tridentate iron chelator providing both effective protection against various types of oxidative stress-induced cellular injury and anticancer action. However, the major limitation of SIH is represented by its labile hydrazone bond that makes it prone to plasma hydrolysis. Recently, nine new SIH analogues derived from aromatic ketones with improved hydrolytic stability were developed. Here we analyzed their antiproliferative potential in MCF-7 breast adenocarcinoma and HL-60 promyelocytic leukemia cell lines. Seven of the tested substances showed greater selectivity than the parent agent SIH towards the latter cancer cell lines compared to non-cancerous H9c2 cardiomyoblast-derived cells. The tested chelators induced a dose-dependent dissipation of the inner mitochondrial membrane potential, an induction of apoptosis as evidenced by Annexin V positivity or significant increases of activities of caspases 3, 7, 8 and 9 and cell cycle arrest. With the exception of nitro group-bearing NHAPI, the studies of iron complexes of the chelators confirmed the crucial role of iron in the mechanism of their antiproliferative action. Finally, all the assayed chelators inhibited the oxidation of ascorbate by iron ions indicating lack of redox activity of the chelator-iron complexes. In conclusion, this study identified several important design criteria for improvement of the antiproliferative selectivity of the aroylhydrazone iron chelators. Several of the novel compounds--in particular the ethylketone-derived HPPI, NHAPI and acetyl-substituted A2,4DHAPI--merit deeper investigation as promising potent and selective anticancer agents.
- MeSH
- aldehydy chemie farmakologie MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- chelátory železa chemie farmakologie MeSH
- deferoxamin farmakologie MeSH
- HL-60 buňky MeSH
- hydrazony chemie farmakologie MeSH
- kaspasy metabolismus MeSH
- ketony chemie MeSH
- kyselina askorbová metabolismus MeSH
- lidé MeSH
- membránový potenciál mitochondrií účinky léků MeSH
- nádorové buněčné linie MeSH
- oxidace-redukce MeSH
- protinádorové látky chemie farmakologie MeSH
- screeningové testy protinádorových léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Anthracycline anticancer drugs (e.g., doxorubicin or daunorubicin) can induce chronic cardiotoxicity and heart failure (HF), both of which are believed to be based on oxidative injury and mitochondrial damage. In this study, molecular and functional changes induced by chronic anthracycline treatment with progression into HF in post-treatment follow-up were analyzed with special emphasis on nuclear factor erythroid 2-related factor 2 (Nrf2) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α) pathways. Chronic cardiotoxicity was induced in rabbits with daunorubicin (3 mg/kg, weekly for 10 weeks), and the animals were followed for another 10 weeks. Echocardiography revealed a significant drop in left ventricular (LV) systolic function during the treatment with marked progression to LV dilation and congestive HF in the follow-up. Although daunorubicin-induced LV lipoperoxidation was found, it was only loosely associated with cardiac performance. Furthermore, although LV oxidized glutathione content was increased, the oxidized-to-reduced glutathione ratio itself remained unchanged. Neither Nrf2, the master regulator of antioxidant response, nor the majority of its target genes showed up-regulation in the study. However, down-regulation of manganese superoxide dismutase and NAD(P)H dehydrogenase [quinone] 1 were observed together with heme oxygenase 1 up-regulation. Although marked perturbations in mitochondrial functions were found, no induction of PGC1α-controlled mitochondrial biogenesis pathway was revealed. Instead, especially in the post-treatment period, an impaired regulation of this pathway was observed along with down-regulation of the expression of mitochondrial genes. These results imply that global oxidative stress need not be a factor responsible for the development of anthracycline-induced HF, whereas suppression of mitochondrial biogenesis might be involved.
- MeSH
- antracykliny toxicita MeSH
- buněčné jádro účinky léků metabolismus MeSH
- daunomycin farmakologie MeSH
- echokardiografie MeSH
- faktor 2 související s NF-E2 biosyntéza MeSH
- funkční vyšetření srdce MeSH
- glutathion metabolismus MeSH
- králíci MeSH
- kvantitativní polymerázová řetězová reakce MeSH
- myokard patologie MeSH
- nemoci srdce chemicky indukované metabolismus MeSH
- oxidační stres účinky léků MeSH
- peroxidace lipidů účinky léků MeSH
- přežití MeSH
- protinádorová antibiotika toxicita MeSH
- srdeční komory účinky léků metabolismus MeSH
- srdeční mitochondrie účinky léků metabolismus MeSH
- transkripční faktory metabolismus MeSH
- troponin T metabolismus MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
