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PloS One 2017Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in...
Peptides containing the asparagine-glycine-arginine (NGR) motif are recognized by CD13/aminopeptidase N (APN) receptor isoforms that are selectively overexpressed in tumor neovasculature. Spontaneous decomposition of NGR peptides can result in isoAsp derivatives, which are recognized by RGD-binding integrins that are essential for tumor metastasis. Peptides binding to CD13 and RGD-binding integrins provide tumor-homing, which can be exploited for dual targeted delivery of anticancer drugs. We synthesized small cyclic NGR peptide-daunomycin conjugates using NGR peptides of varying stability (c[KNGRE]-NH2, Ac-c[CNGRC]-NH2 and the thioether bond containing c[CH2-CO-NGRC]-NH2, c[CH2-CO-KNGRC]-NH2). The cytotoxic effect of the novel cyclic NGR peptide-Dau conjugates were examined in vitro on CD13 positive HT-1080 (human fibrosarcoma) and CD13 negative HT-29 (human colon adenocarcinoma) cell lines. Our results confirm the influence of structure on the antitumor activity and dual acting properties of the conjugates. Attachment of the drug through an enzyme-labile spacer to the C-terminus of cyclic NGR peptide resulted in higher antitumor activity on both CD13 positive and negative cells as compared to the branching versions.
Topics: Antibiotics, Antineoplastic; Cell Line, Tumor; Chromatography, High Pressure Liquid; Chromatography, Reverse-Phase; Cyclization; Daunorubicin; Humans; Oligopeptides; Spectrometry, Mass, Electrospray Ionization
PubMed: 28575020
DOI: 10.1371/journal.pone.0178632 -
ACS Chemical Biology Dec 2022Many small molecule natural products are decorated with sugar moieties that are essential for their biological activity. A considerable number of natural product...
Many small molecule natural products are decorated with sugar moieties that are essential for their biological activity. A considerable number of natural product glycosides and their derivatives are clinically important therapeutics. Anthracyclines like daunorubicin and doxorubicin are examples of valuable glycosylated natural products used in medicine as potent anticancer agents. The sugar moiety, l-daunosamine (a highly modified deoxyhexose), plays a key role in the bioactivity of these molecules as evidenced by semisynthetic anthracycline derivatives such as epirubicin, wherein alteration in the configuration of a single stereocenter of the sugar unit generates a chemotherapeutic drug with lower cardiotoxicity. The nucleotide activated sugar donor that provides the l-daunosamine group for attachment to the natural product scaffold in the biosynthesis of these anthracyclines is dTDP-l-daunosamine. In an system, we have reconstituted the enzymes in the daunorubicin/doxorubicin pathway involved in the biosynthesis of dTDP-l-daunosamine. Through the study of the enzymatic steps in this reconstituted pathway, we have gained several insights into the assembly of this precursor including the identification of a major bottleneck and competing reactions. We carried out kinetic analysis of the aminotransferase that catalyzes a limiting step of the pathway. Our reconstituted pathway also provided a platform to test the combinatorial enzymatic synthesis of other dTDP-activated deoxyhexoses as potential tools for "glycodiversification" of natural products. To this end, we replaced the stereospecific ketoreductase that acts in the last step of dTDP-l-daunosamine biosynthesis with an enzyme from a heterologous pathway with opposite stereospecificity and found that it is active in the pathway, demonstrating the potential for the enzymatic synthesis of nucleotide-activated sugars with regio- and stereospecific tailoring.
Topics: Anthracyclines; Glycosylation; Biosynthetic Pathways; Kinetics; Daunorubicin; Antibiotics, Antineoplastic; Polyketides; Doxorubicin; Carbohydrates; Deoxyribonucleotides; Nucleotides; Biological Products; Sugars
PubMed: 34751552
DOI: 10.1021/acschembio.1c00646 -
International Journal of Molecular... Jan 2021The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs...
The interactions of chemotherapeutic drugs with nanocage protein apoferritin (APO) are the key features in the effective encapsulation and release of highly toxic drugs in APO-based controlled drug delivery systems. The encapsulation enables mitigating the drugs' side effects, collateral damage to healthy cells, and adverse immune reactions. Herein, the interactions of anthracycline drugs with APO were studied to assess the effect of drug lipophilicity on their encapsulation excess and in vitro activity. Anthracycline drugs, including doxorubicin (DOX), epirubicin (EPI), daunorubicin (DAU), and idarubicin (IDA), with lipophilicity from 0.8 to 15, were investigated. We have found that in addition to hydrogen-bonded supramolecular ensemble formation with = 24, there are two other competing contributions that enable increasing under strong polar interactions (APO(DOX)) or under strong hydrophobic interactions (APO(IDA) of the highest efficacy). The encapsulation/release processes were investigated using UV-Vis, fluorescence, circular dichroism, and FTIR spectroscopies. The in vitro cytotoxicity/growth inhibition tests and flow cytometry corroborate high apoptotic activity of APO(drugs) against targeted MDA-MB-231 adenocarcinoma and HeLa cells, and low activity against healthy MCF10A cells, demonstrating targeting ability of nanodrugs. A model for molecular interactions between anthracyclines and APO nanocarriers was developed, and the relationships derived compared with experimental results.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Apoferritins; Cell Line, Tumor; Daunorubicin; Delayed-Action Preparations; Doxorubicin; Drug Delivery Systems; Epirubicin; HeLa Cells; Humans; Hydrophobic and Hydrophilic Interactions; Nanostructures; Neoplasms
PubMed: 33572999
DOI: 10.3390/ijms22031362 -
Journal of Cellular and Molecular... Jun 2019The bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukaemia (AML) and multiple myeloma (MM). We have shown that the critical drug...
The bone marrow (BM) microenvironment contributes to drug resistance in acute myeloid leukaemia (AML) and multiple myeloma (MM). We have shown that the critical drug metabolizing enzymes cytochrome P450 (CYP) 3A4 and cytidine deaminase (CDA) are highly expressed by BM stroma, and play an important role in this resistance to chemotherapy. However, what factors influence the chemoprotective capacity of the BM microenvironment, specifically related to CYP3A4 and CDA expression, are unknown. In this study, we found that the presence of AML cells decreases BM stromal expression of CYP3A4 and CDA, and this effect appears to be at least partially the result of cytokines secreted by AML cells. We also observed that stromal CYP3A4 expression is up-regulated by drugs commonly used in AML induction therapy, cytarabine, etoposide and daunorubicin, resulting in cross-resistance. Cytarabine also up-regulated CDA expression. The up-regulation of CYP3A4 associated with disease control was reversed by clarithromycin, a potent inhibitor of CYP3A4. Our data suggest that minimal residual disease states are characterized by high levels of stromal drug metabolizing enzymes and thus, strong microenvironment-mediated drug resistance. These results further suggest a potential role for clinically targeting drug metabolizing enzymes in the microenvironment.
Topics: Bone Marrow; Bone Marrow Cells; Cell Line; Cell Line, Tumor; Cytarabine; Cytochrome P-450 CYP3A; Daunorubicin; Drug Resistance, Neoplasm; Etoposide; Humans; Inactivation, Metabolic; Leukemia, Myeloid, Acute; Stromal Cells; Tumor Microenvironment; Up-Regulation
PubMed: 30920135
DOI: 10.1111/jcmm.14298 -
Bioactive Materials Jun 2017Daunorubicin hydrochloride is a cell-cycle non-specific antitumor drug with a high therapeutic effect. The present study outlines the fabrication of daunorubicin...
Daunorubicin hydrochloride is a cell-cycle non-specific antitumor drug with a high therapeutic effect. The present study outlines the fabrication of daunorubicin hydrochloride-loaded poly (ε-caprolactone) (PCL) fibrous membranes by melt electrospinning for potential application in localized tumor therapy. The diameters of the drug-loaded fibers prepared with varying concentrations of daunorubicin hydrochloride (1, 5, and 10 wt%) were 2.48 ± 1.25, 2.51 ± 0.78, and 2.49 ± 1.58 μm, respectively. Fluorescence images indicated that the hydrophobic drug was dispersed in the hydrophilic PCL fibers in their aggregated state. The drug release profiles of the drug-loaded PCL melt electrospun fibrous membranes were approximately linear, with slow release rates and long-term release periods, and no observed burst release. The MTT assay was used to examine the cytotoxic effect of the released daunorubicin hydrochloride on HeLa and glioma cells (U87) . The inhibition ratios of HeLa and glioma cells following treatment with membranes prepared with 1, 5, and 10 wt% daunorubicin hydrochloride were 62.69%, 76.12%, and 85.07% and 62.50%, 77.27%, and 84.66%, respectively. Therefore, PCL melt electrospun fibrous membranes loaded with daunorubicin hydrochloride may be used in the local administration of oncotherapy.
PubMed: 29744416
DOI: 10.1016/j.bioactmat.2017.03.003 -
The Journal of Clinical Investigation Nov 1982We have studied the influence of verapamil hydrochloride on the in vitro and in vivo effects of daunorubicin in Ehrlich ascites carcinoma. Daunorubicin-sensitive tumor...
We have studied the influence of verapamil hydrochloride on the in vitro and in vivo effects of daunorubicin in Ehrlich ascites carcinoma. Daunorubicin-sensitive tumor was rendered resistant to daunorubicin by the continuous treatment of sequential generations of tumor-bearing BALB/c mice. The ability of daunorubicin to inhibit [(3)H]uridine and [(3)H]thymidine incorporation and the effect of daunorubicin on the mean survival time of host animals bearing daunorubicin-sensitive and daunorubicin-resistant Ehrlich ascites carcinoma were compared. The addition of verapamil to daunorubicin in vitro reduced the concentration of daunorubicin required to inhibit 50% of DNA and RNA synthesis in the daunorubicin-resistant tumor to that required in the daunorubicin-sensitive tumor, from 6 and 4.4 mug/ml to 1.5 and 1.3 mug/ml, respectively. Verapamil also restored drug sensitivity to daunorubicin-resistant Ehrlich ascites carcinoma in vivo. The 21.7+/-0.7 d mean survival time (MST) of BALB/c mice bearing daunorubicin-resistant tumor treated with daunorubicin alone rose to 44.0+/-0.7 d when the same tumor was treated with verapamil and daunorubicin, P < 0.001. This in vivo effect is specific for daunorubicin-resistant Ehrlich ascites carcinoma, since there is no alteration in MST of BALB/c mice bearing daunorubicin-sensitive or daunorubicin-resistant tumor when they are treated with verapamil alone or when BALB/c mice bearing daunorubicin-sensitive tumor are treated with daunorubicin and verapamil.
Topics: Animals; Carcinoma, Ehrlich Tumor; Cell Transformation, Neoplastic; DNA; Daunorubicin; Dose-Response Relationship, Drug; Drug Resistance; Mice; Mice, Inbred BALB C; RNA; Verapamil
PubMed: 6182160
DOI: 10.1172/jci110702 -
International Journal of Nanomedicine 2019Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. The...
Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-β1 (TGF-β1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.
Topics: A549 Cells; Animals; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Movement; Daunorubicin; Diosgenin; Drug Delivery Systems; Female; Humans; Liposomes; Lung Neoplasms; Matrix Metalloproteinase 2; Mice, Inbred BALB C; Mice, Nude; Neoplasm Metastasis; Oligopeptides; Particle Size; Static Electricity; Wound Healing
PubMed: 31239668
DOI: 10.2147/IJN.S194304 -
Medicine Jun 2020To ascertain the efficacy and safety of daunorubicin combined with cytarabine comparing with idarubicin combined with cytarabine as a standard induction therapy for... (Comparative Study)
Comparative Study Meta-Analysis
The efficacy and safety of daunorubicin versus idarubicin combined with cytarabine for induction therapy in acute myeloid leukemia: A meta-analysis of randomized clinical trials.
OBJECTIVE
To ascertain the efficacy and safety of daunorubicin combined with cytarabine comparing with idarubicin combined with cytarabine as a standard induction therapy for acute Myeloid leukemia by a meta-analysis.
METHODS
The randomized controlled trials included were retrieved from PubMed, Embase, and Cochrane library. We evaluated and cross-checked the randomized clinical trials (RCTs) comparing daunorubicin combined with cytarabine (DA) and idarubicin combined with cytarabine (IA) by two reviewers independently according to Cochrane Handbook for Systematic Reviewers of Interventions. The data of meta-analysis was conducted using Review Manager 5.3 and Stata 12.0 software.
RESULTS
A total of 6 studies containing 3140 patients were included. The primary outcomes were complete remission (CR), CR in one course (CR1), CR in two courses (CR2), overall survival (OS), and relapse rate. The secondary outcomes included adverse events and cytogenetic risk in subgroup analyses. IA showed a statistically significant in CR (RR = 1.05; 95%CI = 1.00-1.09, P = .03) and CR1 (RR = 1.11; 95%CI = 1.04-1.18, P = .003), but not in CR2 (RR = 0.97; 95%CI = 0.77-1.24, P = .83), and relapse rate (RR = 1.08; 95%CI = 0.98-1.43, P = .08). In high dose daunorubicin group, OS was significantly improved with IA compared to DA (HR = 0.89, 95%CI = 0.8-1.0, P = .041, I = 0). At grade 3/4 adverse events, the difference between IA and DA was not statistically significant (infection, P = .28; cardiac toxicity, P = .15; bleeding, P = .29). In the subgroup analysis, the genotypes of the IA and DA groups were not statistically significant for comparison of CR between the two groups (P = .07).
CONCLUSION
This meta-analysis showed that IA had a better efficacy in the treatment of acute myeloid leukemia than DA, even with increased doses of DA. The OS of a standard dose of IA patients was longer than that of DA patients. Our research shows that anthracycline dose intensification of daunorubicin is of no clinically relevant benefit in AML patients comparing with a standard dose of IA. When it comes to adverse drug reactions, it is not a significant difference. Therefore, in clinical practice, IA should be the first choice for induction regimen in patients with acute myeloid leukemia.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Female; Humans; Idarubicin; Induction Chemotherapy; Leukemia, Myeloid, Acute; Male; Middle Aged; Randomized Controlled Trials as Topic; Recurrence; Remission Induction; Safety; Survival Analysis; Topoisomerase II Inhibitors; Treatment Outcome; United States; Young Adult
PubMed: 32541448
DOI: 10.1097/MD.0000000000020094 -
Nanomedicine : Nanotechnology, Biology,... Aug 2019Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to...
Patients with acute myeloid leukemia have a very poor prognosis related to a high rate of relapse and drug-related toxicity. The ability of leukemia stem cells (LSCs) to survive chemotherapy is primarily responsible for relapse, and eliminating LSCs is ultimately essential for cure. We developed novel disulfide-crosslinked CLL1-targeting micelles (DC-CTM), which can deliver high concentrations of daunorubicin (DNR) into both bulk leukemia cells and LSCs. Compared to free DNR, DC-CTM-DNR had a longer half-life, increased DNR area under the curve concentration by 11-fold, and exhibited a superior toxicity profile. In patient-derived AML xenograft models, DC-CTM-DNR treatment led to significant decreases in AML engraftment and impairment of secondary transplantation compared to control groups. Collectively, we demonstrate superior anti-LSC/AML efficacy, and preferable pharmacokinetic and toxicity profiles of DC-CTM-DNR compared to free DNR. DC-CTM-DNR has the potential to significantly improve treatment outcomes and reduce therapy-related morbidity and mortality for patients with AML.
Topics: Animals; Cross-Linking Reagents; Daunorubicin; Disulfides; Humans; Lectins, C-Type; Leukemia, Myeloid, Acute; Mice, Inbred BALB C; Micelles; Nanoparticles; Neoplastic Stem Cells; Rats, Sprague-Dawley
PubMed: 31055076
DOI: 10.1016/j.nano.2019.04.007 -
Biochimie Dec 2012DNA supercoiling plays a critical role in certain essential DNA transactions, such as DNA replication, recombination, and transcription. For this reason, exploring...
DNA supercoiling plays a critical role in certain essential DNA transactions, such as DNA replication, recombination, and transcription. For this reason, exploring energetics of DNA supercoiling is fundamentally important for understanding its biological functions. In this paper, using a unique property of DNA intercalators, such as ethidium bromide and daunorubicin, which bind to supercoiled, nicked, and relaxed DNA templates with different DNA-binding enthalpies, we determined DNA supercoiling enthalpy of plasmid pXXZ6, a 4.5 kb plasmid to be about 11.5 kcal/mol per linking number change. This determination allowed us to partition the DNA supercoiling free energy into enthalpic and entropic contributions where the unfavorable DNA supercoiling free energy exclusively originated from the large positive supercoiling enthalpy and was compensated by a large, favorable entropy term (TΔS).
Topics: Algorithms; Calorimetry; DNA, Superhelical; Daunorubicin; Entropy; Ethidium; Intercalating Agents; Kinetics; Models, Chemical; Models, Molecular; Nucleic Acid Conformation; Plasmids; Thermodynamics
PubMed: 22940593
DOI: 10.1016/j.biochi.2012.08.002