Idarubicin

BackgroundMRSA is a major concern in community settings and in health care. The emergence of biofilms and persister cells substantially increases its antimicrobial resistance. It is very urgent to develop new antimicrobials to solve this problem.ObjectiveIdarubicin was profiled to assess its antimicrobial effects in vitro and in vivo, and the underlying mechanisms.MethodsWe investigated the antimicrobial effects of idarubicin against MRSA by time-kill analysis. The antibiofilm efficacy of idarubicin was assessed by crystal violet and XTT staining, followed by laser confocal microscopy observation. The mechanisms underlying the antimicrobial effects were studied by transmission electron microscopy, all-atom molecular dynamic simulations, SYTOX staining, surface plasma resonance, and DNA gyrase inhibition assay. Further, we addressed the antimicrobial efficacy in wound and subcutaneous abscess infection in vivo.ResultsIdarubicin kills MRSA cells by disrupting the lipid bilayers and interrupting the DNA topoisomerase IIA subunits, and idarubicin shows synergistic antimicrobial effects with fosfomycin. Through synergy with a single dose treatment fosfomycin and the addition of the cell protector amifostine, the cytotoxicity and cardiotoxicity of idarubicin were significantly reduced without affecting its antimicrobial effects. Idarubicin alone or in combination with fosfomycin exhibited considerable efficacy in a subcutaneous abscess mouse model of MRSA infection. In addition, idarubicin also showed a low probability of causing resistance and good postantibiotic effects.ConclusionsIdarubicin and its analogs have the potential to become a new class of antimicrobials for the treatment of MRSA-related infections.

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

Mutations in DNMT3A encoding DNA methyltransferase 3A were recently described in patients with acute myeloid leukemia. To assess their prognostic significance, we determined the mutational status of DNMT3A exon 23 in 288 patients with AML excluding acute promyelocytic leukemia, aged from 18 to 65 years and treated in Toulouse University Hospital. A mutation was detected in 39 patients (13.5%). All DNMT3A exon 23+ patients had intermediate-risk cytogenetics. Mutations significantly correlated with a higher WBC count (p less than 0.001), NPM1 and FLT3-ITD mutations (p=0.027). DNMT3A mutations were conserved through xenotransplantation in immunodeficient mice. No difference in outcome between DNMT3A exon 23+ and DNMT3A exon 23- patients was found even if the results were stratified by NPM1 or FLT3-ITD status. However, DNMT3A exon 23+ patients had better median DFS (not reached vs 11.6 months, p=0.009) and OS (not reached vs 14.3 months, p=0.005) as compared to DNMT3A exon 23- patients when treated with idarubicin, whereas patients treated with daunorubicin had similar outcome regardless the DNMT3A status. This study shows that DNMT3A mutations have no impact on outcome but could be a predictive factor for response to idarubicin and thus, could have a direct influence in the way AML patients should be managed.

Idarubicine is a mainstay of the treatment strategy for hematological cancer. The literature lacks stability data that comply with current preparation practices and recommendations for conducting stability studies. The aim of the present work is to establish the stability of idarubicin preparations diluted in polyolefin-type bags (Freeflex + ®) for intravenous administration in hematological clinical settings. Preparations were produced by diluting Zavedos® idarubicin in Freeflex + ® bags containing 0.9% sodium chloride (NaCl) or 5% dextrose (Dex) at concentrations of 0.04 mg/mL and 0.2 mg/mL. These preparations were stored at 5 ± 3 °C or 22 ± 3 °C. Three bags were prepared to evaluate each condition, for a total of 24 bags. To assess chemical stability, a stability-indicating high pressure liquid chromatography-ultraviolet/visible diode array detector assay was used. Samples were assayed on days D0, D1, D2, D7, D15, D22 and D30. A physical stability study was carried out on days D0, D15 and D30, looking for visible and sub-visible particles, measuring pH and osmolality. During the study, sample concentrations remained above 95% of the initial concentration, and no degradation products were detected. No color change or precipitation were observed with the naked eye. Sub-visible particles count remained below recommended limits. The pH and osmolality values remained unchanged from D0. This study demonstrates the stability of idarubicin, diluted to concentrations between 0.04 and 0.2 mg/mL in solutions of 0.9% NaCl and 5% Dex, stored at 5 ± 3 °C or 22 ± 3 °C for 30 days.