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Journal of the American Academy of... Jan 2022
Topics: Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Erythema; Humans; Leukemia, Myeloid, Acute; Retrospective Studies
PubMed: 33539850
DOI: 10.1016/j.jaad.2021.01.096 -
International Journal of Nanomedicine 2020The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increase risk of transformation...
INTRODUCTION
The myelodysplastic syndromes (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increase risk of transformation to acute myeloid leukemia (AML). Daunorubicin (DNR) is an indispensable drug for the treatment of MDS and AML. However, its side effects including cardiac toxicity and bone marrow suppression severely limit clinical application. Many researches reported high expression of CD123 antigen on high-risk MDS cells, so we constructed a novel drug delivery system comprising daunorubicin-loaded CdTe QDs conjugated with anti-CD123 mAbs (DNR-CdTe-CD123) to develop targeted combination chemotherapy for MDS.
METHODS
CdTe conjugated antiCD123 through amide bond, co-loaded with DNR with electrostatic bonding. Then, we determined characterization and release rate of DNR-CdTe-CD123. The therapeutic effect and side effect of drug delivery system were evaluated through in vitro and in vivo experiments.
RESULTS
CdTe showed appropriate diameter and good dispersibility and DNR was loaded into CdTes with high encapsulation efficiency and drug loading. The maximum drug loading and encapsulation efficiency were 42.08 ± 0.64% and 74.52 ± 1.81%, respectively, at DNR concentration of 0.2mg/mL and anti-CD123 mAbs volume of 5ul (100ug/mL). Flow cytometry (FCM) showed that CD123 antigen was highly expressed on MUTZ-1 cells, and its expression rate was 72.89 ± 10.67%. In vitro experiments showed that the inhibition rate and apoptosis rate of MUTZ-1 cells treated with DNR-CdTe-CD123 were higher than those in the other groups (<0.05). Compared with the other groups, the level of apoptosis-related protein (P53, cleaved caspase-9, Bax and cleaved caspase-3) were upregulated in DNR-CdTe-CD123 group (<0.05). In vivo experiments, DNR-CdTe-CD123 can effectively inhibit the tumor growth of MDS-bearing nude mice and reduce the side effects of DNR on myocardial cells.
CONCLUSION
The system of DNR-CdTe-CD123 enhances the therapeutic effects and reduce the side effects of DNR, thus providing a novel platform for MDS treatment.
Topics: Animals; Antibodies, Monoclonal; Apoptosis; Cadmium Compounds; Caspase 3; Daunorubicin; Drug Delivery Systems; Humans; Interleukin-3 Receptor alpha Subunit; Mice, Inbred BALB C; Mice, Nude; Myelodysplastic Syndromes; Quantum Dots; Tellurium; Toxicity Tests; Xenograft Model Antitumor Assays
PubMed: 32021192
DOI: 10.2147/IJN.S233395 -
Applied Microbiology and Biotechnology Dec 2024Streptomyces peucetius ATCC 27952 is known to produce a variety of secondary metabolites, including two important antitumor anthracyclines: daunorubicin and doxorubicin....
Streptomyces peucetius ATCC 27952 is known to produce a variety of secondary metabolites, including two important antitumor anthracyclines: daunorubicin and doxorubicin. Identification of peucemycin and 25-hydroxy peucemycin (peucemycin A), as well as their biosynthetic pathway, has expanded its biosynthetic potential. In this study, we isolated a new peucemycin derivative and identified it as 19-hydroxy peucemycin (peucemycin B). Its antibacterial activity was lower than those of peucemycin and peucemycin A. On the other hand, this newly identified peucemycin derivative had higher anticancer activity than the other two compounds for MKN45, NCI-H1650, and MDA-MB-231 cancer cell lines with IC values of 76.97 µM, 99.68 µM, and 135.2 µM, respectively. Peucemycin biosynthetic gene cluster revealed the presence of a SARP regulator named PeuR whose role was unknown. The presence of the TTA codon in the peuR and the absence of global regulator BldA in S. peucetius reduced its ability to regulate the peucemycin biosynthetic gene cluster. Hence, different mutants harboring these genes were prepared. S. peucetius bldA25 harboring bldA produced 1.75 times and 1.77 times more peucemycin A (11.8 mg/L) and peucemycin B (21.2 mg/L), respectively, than the wild type. On the other hand, S. peucetius R25 harboring peuR produced 1.86 and 1.79 times more peucemycin A (12.5 mg/L) and peucemycin B (21.5 mg/L), respectively, than the wild type. Finally, strain S. peucetius bldAR25 carrying bldA and peuR produced roughly 3.52 and 2.63 times more peucemycin A (23.8 mg/L) and peucemycin B (31.5 mg/L), respectively, than the wild type. KEY POINTS: • This study identifies a new peucemycin derivative, 19-hydroxy peucemycin (peucemycin B). • The SARP regulator (PeuR) acts as a positive regulator of the peucemycin biosynthetic gene cluster. • The overexpression of peuR and heterologous expression of bldA increase the production of peucemycin derivatives.
Topics: Daunorubicin; Doxorubicin; Anthracyclines; Antibiotics, Antineoplastic; Streptomyces
PubMed: 38217253
DOI: 10.1007/s00253-023-12923-4 -
Frontiers in Cellular and Infection... 2022Anticancer drug efficacy is linked to the gut microbiota's composition, and there is a dire need to better understand these interactions for personalized medicine....
BACKGROUND
Anticancer drug efficacy is linked to the gut microbiota's composition, and there is a dire need to better understand these interactions for personalized medicine. microbiota models are promising tools for studies requiring controlled and repeatable conditions. We evaluated the impact of two anticancer drugs on human feces in the MiniBioReactor Array (MBRA) microbiota system.
METHODS
The MBRA is a single-stage continuous-flow culture model, hosted in an anaerobic chamber. We evaluated the effect of a 5-day treatment with hydroxycarbamide or daunorubicine on the fecal bacterial communities of two healthy donors. 16S microbiome profiling allowed analysis of microbial richness, diversity, and taxonomic changes.
RESULTS
In this host-free setting, anticancer drugs diversely affect gut microbiota composition. Daunorubicin was associated with significant changes in alpha- and beta-diversity as well as in the ratio of Firmicutes/Bacteroidetes in a donor-dependent manner. The impact of hydroxycarbamide on microbiota composition was not significant.
CONCLUSION
We demonstrated, for the first time, the impact of anticancer drugs on human microbiota composition, in a donor- and molecule-dependent manner in an human microbiota model. We confirm the importance of personalized studies to better predict drug-associated-dysbiosis , linked to the host's response to treatment.
Topics: Daunorubicin; Feces; Gastrointestinal Microbiome; Humans; Microbiota; Pilot Projects; RNA, Ribosomal, 16S
PubMed: 35719352
DOI: 10.3389/fcimb.2022.886447 -
Blood May 1997The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular...
The U-A10 cell line, a doxorubicin-selected variant of human U-937 myeloid leukemia cells, exhibits a redistribution of anthracyclines into a expanded vesicular compartment. The acidic nature of this compartment was confirmed by vital staining with a pH sensitive dye, LysoSensor yellow/blue DND-160. Identification of the vesicular compartment was performed by immunofluorescence analysis. Staining for the LAMP-1 and LAMP-2 antigens showed that the vesicles are enlarged lysosomes that are eccentrically placed near the nucleus of U-A10 cells. By contrast, the expression of the multidrug resistance-associated protein and the P-glycoprotein was observed predominately on the plasma membrane of the drug-resistant cells. The accumulation of daunorubicin into cellular compartments was quantified using radiolabeled drug. Exposing cells to 3[H]-daunorubicin and then isolating intact nuclei showed that nuclei from U-A10 cells accumulated twofold to threefold less anthracycline than nuclei from U-937 cells. However, when nuclei were isolated first and then exposed to 3[H]-daunorubicin, little difference in net nuclear drug accumulation was detected. Cytoplasts prepared from U-A10 and U-937 cells were exposed to 3[H]-daunorubicin to measure cytoplasmic drug accumulation. At external daunorubicin concentrations of 100 ng/mL or higher, cytoplasts from U-A10 cells accumulated significantly more daunorubicin than cytoplasts from U-937 cells. Moreover, studies with the lysosomotropic agent chloroquine showed that U-A10 cells accumulated twofold more chloroquine and showed twofold enhanced sensitivity to this agent as compared with parental U-937 cells. Fluorescence microscopy showed that chloroquine affects vesicular anthracycline sequestration in U-A10 cells with an associated increase in daunorubicin nuclear fluorescence. Although chloroquine did not alter anthracycline cytotoxicity in parental cells, it restored daunorubicin and doxorubicin sensitivity to U-A10 cells. Taken together, these studies demonstrate that U-A10 cells exhibit a redistribution of the lysosomal compartment. The trapping of drug into an expanded acidic vesicular compartment results in decreased nuclear drug accumulation and decreased cytotoxicity. Lysosomotropic agents, such as chloroquine, warrant further study as modulators of this acquired drug-resistance phenotype.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Antibiotics, Antineoplastic; Antigens, CD; Antigens, Neoplasm; Biological Transport; Biomarkers; Chloroquine; Cytoplasm; Daunorubicin; Doxorubicin; Drug Resistance, Neoplasm; Humans; Hydrogen-Ion Concentration; Leukemia, Myeloid; Lymphoma, Large B-Cell, Diffuse; Lysosomal Membrane Proteins; Lysosomes; Membrane Glycoproteins; Microscopy, Fluorescence; Neoplasm Proteins; Selection, Genetic; Tumor Cells, Cultured
PubMed: 9160680
DOI: No ID Found -
Journal of Controlled Release :... Dec 2013Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of...
Doxorubicin (DXR) and daunorubicin (DNR) inhibit hypoxia-inducible factor-1 (HIF-1) transcriptional activity by blocking its binding to DNA. Intraocular injections of DXR or DNR suppressed choroidal and retinal neovascularization (NV), but also perturbed retinal function as demonstrated by electroretinograms (ERGs). DXR was conjugated to novel copolymers of branched polyethylene glycol and poly(sebacic acid) (DXR-PSA-PEG3) and formulated into nanoparticles that when placed in aqueous buffer, slowly released small DXR-conjugates. Intraocular injection of DXR-PSA-PEG3 nanoparticles (1 or 10 μg DXR content) reduced HIF-1-responsive gene products, strongly suppressed choroidal and retinal NV, and did not cause retinal toxicity. In transgenic mice that express VEGF in photoreceptors, intraocular injection of DXR-PSA-PEG3 nanoparticles (10 μg DXR content) suppressed NV for at least 35 days. Intraocular injection of DXR-PSA-PEG3 nanoparticles (2.7 mg DXR content) in rabbits resulted in sustained DXR-conjugate release with detectable levels in aqueous humor and vitreous for at least 105 days. This study demonstrates a novel HIF-1-inhibitor-polymer conjugate formulated into controlled-release particles that maximizes efficacy and duration of activity, minimizes toxicity, and provides a promising new chemical entity for treatment of ocular NV.
Topics: Animals; Antibiotics, Antineoplastic; Daunorubicin; Delayed-Action Preparations; Doxorubicin; Hypoxia-Inducible Factor 1; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nanoparticles; Polyethylene Glycols; Rabbits; Retina; Retinal Neovascularization
PubMed: 24126220
DOI: 10.1016/j.jconrel.2013.10.008 -
Journal of Bacteriology Mar 1992Two DNA fragments, ric1 and ric2, were isolated from the Streptomyces peucetius 7600 mutant, which produces daunorubicin and doxorubicin, on the basis of their abilities...
Two DNA fragments, ric1 and ric2, were isolated from the Streptomyces peucetius 7600 mutant, which produces daunorubicin and doxorubicin, on the basis of their abilities to confer doxorubicin and daunorubicin resistance to Streptomyces lividans. These two fragments are unrelated by restriction mapping and do not show any homology by Southern analysis, yet both of them increase the level of resistance 10-fold in transformed S. lividans. Functional analysis revealed that ric1 also contains two genes of daunorubicin biosynthesis: one coding for the aklavinone C-11 hydroxylase and the other corresponding to the putative dnrR2 regulatory gene of wild-type S. peucetius ATCC 29050 (K. J. Stutzman-Engwall, S. L. Otten, and C. R. Hutchinson, J. Bacteriol. 174:144-154, 1992). Northern (RNA) blot experiments, performed with a ric1 fragment containing daunorubicin-doxorubicin resistance gene(s), revealed a transcript of about 2,100 nucleotides that is present only during the phase of anthracycline metabolite production. The amount of this transcript is higher in strain 7600 than in strain 7900, a mutant which produces 5-fold more daunorubicin and 10-fold less doxorubicin than 7600. Furthermore, two 7900-derived blocked mutants, 8600 and 9700, do not express the 2,100-nucleotide transcript in spite of the absence of gross rearrangements in the ric1 region such as occur with the 7900 parental strain.
Topics: Cloning, Molecular; Daunorubicin; Doxorubicin; Drug Resistance, Microbial; Gene Expression Regulation, Bacterial; Genes, Regulator; Models, Biological; Mutation; Naphthacenes; Nucleic Acid Hybridization; RNA Precursors; Restriction Mapping; Streptomyces; Transcription, Genetic
PubMed: 1537806
DOI: 10.1128/jb.174.5.1641-1646.1992 -
Progress in Biophysics and Molecular... 1986
Review
Topics: Adenosine Triphosphate; Biological Transport; Calcium; Cell Division; Cell Survival; Daunorubicin; Doxorubicin; Electric Conductivity; Electron Transport; Free Radicals; Hydrogen-Ion Concentration; Mitochondria; Oxidation-Reduction; Oxygen Consumption; Permeability; Phospholipases A; Superoxides
PubMed: 3029807
DOI: 10.1016/0079-6107(86)90002-7 -
Journal of Bacteriology Jan 1992Two DNA segments, dnrR1 and dnrR2, from the Streptomyces peucetius ATCC 29050 genome were identified by their ability to stimulate secondary metabolite production and...
Two DNA segments, dnrR1 and dnrR2, from the Streptomyces peucetius ATCC 29050 genome were identified by their ability to stimulate secondary metabolite production and resistance. When introduced into the wild-type ATCC 29050 strain, the 2.0-kb dnrR1 segment caused a 10-fold overproduction of epsilon-rhodomycinone, a key intermediate of daunorubicin biosynthesis, whereas the 1.9-kb dnrR2 segment increased production of both epsilon-rhodomycinone and daunorubicin 10- and 2-fold, respectively. In addition, the dnrR2 segment restored high-level daunorubicin resistance to strain H6101, a daunorubicin-sensitive mutant of S. peucetius subsp. caesius ATCC 27952. Analysis of the sequence of the dnrR1 fragment revealed the presence of two closely situated open reading frames, dnrI and dnrJ, whose deduced products exhibit high similarity to the products of several other Streptomyces genes that have been implicated in the regulation of secondary metabolism. Insertional inactivation of dnrI in the ATCC 29050 strain with the Tn5 kanamycin resistance gene abolished epsilon-rhodomycinone and daunorubicin production and markedly decreased resistance to daunorubicin. Sequence comparison between the products of dnrIJ and the products of the Streptomyces coelicolor actII-orf4, afsR, and redD-orf1 genes and of the Streptomyces griseus strS, the Saccharopolyspora erythraea eryC1, and the Bacillus stearothermophilus degT genes reveals two families of putative regulatory genes. The members of the DegT, DnrJ, EryC1, and StrS family exhibit some of the features characteristic of the protein kinase (sensor) component of two-component regulatory systems from other bacteria (even though none of the sequences of these four proteins show a significant overall or regional similarity to such protein kinases) and have a consensus helix-turn-helix motif typical of DNA binding proteins. A helix-turn-helix motif is also present in two of the proteins of the other family, AfsR and RedD-Orf1. Both sets of Streptomyces proteins are likely to be trans-acting factors involved in regulating secondary metabolism.
Topics: Amino Acid Sequence; Anthracyclines; Antibiotics, Antineoplastic; Base Sequence; Daunorubicin; Drug Resistance, Microbial; Gene Expression; Molecular Sequence Data; Mutagenesis, Insertional; Protein Conformation; Restriction Mapping; Sequence Homology, Nucleic Acid; Streptomyces; Transformation, Genetic
PubMed: 1729206
DOI: 10.1128/jb.174.1.144-154.1992 -
Cancer Chemotherapy and Pharmacology Jul 2019Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine... (Comparative Study)
Comparative Study
PURPOSE
Daunorubicin can induce left ventricular dysfunction and QT interval prolongation. This study assessed the effects of CPX-351, a liposomal encapsulation of cytarabine and daunorubicin, on cardiac repolarization.
METHODS
Twenty-six adults with acute leukemia were treated with CPX-351 for 1-2 induction cycles and ≤ 4 consolidation cycles. The primary endpoint was mean change in QTcF from baseline.
RESULTS
Mean QTcF changes were < 10 ms at all time points. No clinically meaningful effects on heart rate, QRS interval, PR interval, or QTcB were observed. Estimated mean half-lives for total cytarabine and daunorubicin were > 30 h. Thirteen (50%) patients achieved remission. The most common adverse events were febrile neutropenia, fatigue, and nausea.
CONCLUSIONS
The cytarabine and daunorubicin in CPX-351 liposomes were metabolized and excreted similarly to conventional formulation; however, plasma pharmacokinetics were altered. CPX-351 did not prolong the QT interval, suggesting that CPX-351 may induce less cardiotoxicity than previously reported for conventional daunorubicin.
TRIAL REGISTRATION
Clinicaltrials.gov identifier: NCT02238925.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Drug Combinations; Female; Half-Life; Humans; Leukemia, Myeloid, Acute; Liposomes; Male; Middle Aged; Treatment Outcome
PubMed: 31098682
DOI: 10.1007/s00280-019-03856-9