Daunomycin is a chemotherapeutic agent widely used for the treatment of leukemia, but its toxicity toward healthy dividing cells limits its clinical use and its production by fermentation. Herein, we describe the development of a specialized cultivation medium for daunomycin production, including a shift to oil rather than sugar as the primary carbon source. This achieved an almost threefold increase in daunomycin yields, reaching 5.5-6.0 g/L. Daunomycin produced in the oil-based medium was predominantly found in the solid sediment, whereas that produced in the sugar-based medium was mostly soluble. The oil-based medium thus induces an autonomous daunomycin-resistance mechanism involving biogenic nanoparticle formation. The characterization of the nanoparticles confirmed the incorporation of iron and daunomycin, indicating that this approach has the potential to mitigate cytotoxicity while improving yields. The presence of proteins associated with iron homeostasis and oxidative stress responses revealed the ability of the production strain to adapt to high iron concentrations. Our findings provide insight into the mechanisms of biogenic nanoparticle formation and the optimization of cultivation processes. Further investigation will help to refine microbial production systems for daunomycin and also broaden the application of similar strategies for the synthesis of other therapeutically important compounds.

• Klíčová slova
• Streptomyces coeruleorubidus, anthracyclines, daunomycin-iron organic complex, iron chelators, medium optimization, production strain development, vivianite,
• Publikační typ
• časopisecké články MeSH

BACKGROUND AND PURPOSE: The clinical utility of anthracycline antineoplastic drugs is limited by the risk of cardiotoxicity, which has been traditionally attributed to iron-mediated production of reactive oxygen species (ROS). EXPERIMENTAL APPROACH: The aims of this study were to examine the strongly lipophilic iron chelator, salicylaldehyde isonicotinoyl hydrazone (SIH), for its ability to protect rat isolated cardiomyocytes against the toxicity of daunorubicin (DAU) and to investigate the effects of SIH on DAU-induced inhibition of proliferation in a leukaemic cell line. Cell toxicity was measured by release of lactate dehydrogenase and staining with Hoechst 33342 or propidium iodide and lipid peroxidation by malonaldehyde formation. KEY RESULTS: SIH fully protected cardiomyocytes against model oxidative injury induced by hydrogen peroxide exposure. SIH also significantly but only partially and with no apparent dose-dependency, reduced DAU-induced cardiomyocyte death. However, the observed protection was not accompanied by decreased lipid peroxidation. In the HL-60 acute promyelocytic leukaemia cell line, SIH did not blunt the antiproliferative efficacy of DAU. Instead, at concentrations that reduced DAU toxicity to cardiomyocytes, SIH enhanced the tumoricidal action of DAU. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that iron is most likely involved in anthracycline cardiotoxicity and that iron chelation has protective potential, but apparently through mechanism(s) other than by inhibition of ROS-induced injury. In addition to cardioprotection, iron chelation may have considerable potential to improve the therapeutic action of anthracyclines by enhancing their anticancer efficiency and this potential warrants further investigation.

• MeSH
• akutní promyelocytární leukemie metabolismus   patologie   MeSH
• aldehydy farmakologie   MeSH
• časové faktory MeSH
• chelátory železa farmakologie   MeSH
• cytoprotekce MeSH
• daunomycin toxicita   MeSH
• HL-60 buňky MeSH
• hydrazony farmakologie   MeSH
• kardiomyocyty účinky léků   metabolismus   patologie   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• malondialdehyd metabolismus   MeSH
• novorozená zvířata MeSH
• oxidační stres účinky léků   MeSH
• peroxidace lipidů účinky léků   MeSH
• potkani Wistar MeSH
• proliferace buněk účinky léků   MeSH
• protinádorová antibiotika toxicita   MeSH
• viabilita buněk účinky léků   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• aldehydy MeSH
• chelátory železa MeSH
• daunomycin MeSH
• hydrazony MeSH
• malondialdehyd MeSH
• protinádorová antibiotika MeSH
• salicylaldehyde isonicotinoyl hydrazone MeSH Prohlížeč