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Journal of the Royal Society, Interface Aug 2017Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes...
Daunorubicin is extensively used in chemotherapy for diverse types of cancer. Over the years, evidence has suggested that the mechanisms by which daunorubicin causes cytotoxic effects are also associated with interactions at the membrane level. The aim of the present work was to study the interplay between daunorubicin and mimetic membrane models composed of different ratios of 1,2-dimyristoyl--glycero--phosphocholine (DMPC), sphingomyelin (SM) and cholesterol (Chol). Several biophysical parameters were assessed using liposomes as mimetic model membranes. Thereby, the ability of daunorubicin to partition into lipid bilayers, its apparent location within the membrane and its effect on membrane fluidity were investigated. The results showed that daunorubicin has higher affinity for lipid bilayers composed of DMPC, followed by DMPC : SM, DMPC : Chol and lastly by DMPC : SM : Chol. The addition of SM or Chol into DMPC membranes not only increases the complexity of the model membrane but also decreases its fluidity, which, in turn, reduces the amount of anticancer drug that can partition into these mimetic models. Fluorescence quenching studies suggest a broad distribution of the drug across the bilayer thickness, with a preferential location in the phospholipid tails. The gathered data support that daunorubicin permeates all types of membranes to different degrees, interacts with phospholipids through electrostatic and hydrophobic bonds and causes alterations in the biophysical properties of the bilayers, namely in membrane fluidity. In fact, a decrease in membrane fluidity can be observed in the acyl region of the phospholipids. Ultimately, such outcomes can be correlated with daunorubicin's biological action, where membrane structure and lipid composition have an important role. In fact, the results indicate that the intercalation of daunorubicin between the phospholipids can also take place in rigid domains, such as rafts that are known to be involved in different receptor processes, which are important for cellular function.
Topics: Animals; Cell Membrane; Cell Membrane Permeability; Daunorubicin; Humans; Membrane Lipids; Membranes, Artificial; Models, Chemical
PubMed: 28855387
DOI: 10.1098/rsif.2017.0408 -
Proceedings of the National Academy of... Oct 2000The binding interactions of (-)-daunorubicin (WP900), a newly synthesized enantiomer of the anticancer drug (+)-daunorubicin, with right- and left-handed DNA, have been...
The binding interactions of (-)-daunorubicin (WP900), a newly synthesized enantiomer of the anticancer drug (+)-daunorubicin, with right- and left-handed DNA, have been studied quantitatively by equilibrium dialysis, fluorescence spectroscopy, and circular dichroism. (+)-Daunorubicin binds selectively to right-handed DNA, whereas the enantiomeric WP900 ligand binds selectively to left-handed DNA. Further, binding of the enantiomeric pair to DNA is clearly chirally selective, and each of the enantiomers was found to act as an allosteric effector of DNA conformation. Under solution conditions that initially favored the left-handed conformation of [poly(dGdC)](2), (+)-daunorubicin allosterically converted the polynucleotide to a right-handed intercalated form. In contrast, under solution conditions that initially favored the right-handed conformation of [poly(dGdC)](2), WP900 converted the polynucleotide to a left-handed form. Molecular dynamics studies by using the amber force field resulted in a stereochemically feasible model for the intercalation of WP900 into left-handed DNA. The chiral selectivity observed for the DNA binding of the daunorubicin/WP900 enantiomeric pair is far greater than the selectivity previously reported for a variety of chiral metal complexes. These results open a new avenue for the rational design of potential anticancer agents that target left-handed DNA.
Topics: Allosteric Regulation; Base Sequence; DNA; Daunorubicin; Models, Molecular; Stereoisomerism
PubMed: 11027298
DOI: 10.1073/pnas.200221397 -
International Journal of Nanomedicine 2016To minimize the side effects and the multidrug resistance (MDR) arising from daunorubicin (DNR) treatment of malignant lymphoma, a chemotherapy formulation of...
To minimize the side effects and the multidrug resistance (MDR) arising from daunorubicin (DNR) treatment of malignant lymphoma, a chemotherapy formulation of cysteamine-modified cadmium tellurium (Cys-CdTe) quantum dots coloaded with DNR and gambogic acid (GA) nanoparticles (DNR-GA-Cys-CdTe NPs) was developed. The physical property, drug-loading efficiency and drug release behavior of these DNR-GA-Cys-CdTe NPs were evaluated, and their cytotoxicity was explored by 3-[4,5-dimethylthiazol-2-y1]-2,5-diphenyltetrazolium bromide assay. These DNR-GA-Cys-CdTe NPs possessed a pH-responsive behavior, and displayed a dose-dependent antiproliferative activity on multidrug-resistant lymphoma Raji/DNR cells. The accumulation of DNR inside the cells, revealed by flow cytometry assay, and the down-regulated expression of P-glycoprotein inside the Raji/DNR cells measured by Western blotting assay indicated that these DNR-GA-Cys-CdTe NPs could minimize the MDR of Raji/DNR cells. This multidrug delivery system would be a promising strategy for minimizing MDR against the lymphoma.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antineoplastic Agents; Cadmium Compounds; Cell Line, Tumor; Cysteamine; Daunorubicin; Dose-Response Relationship, Drug; Drug Liberation; Drug Resistance, Multiple; Female; Humans; Hydrogen-Ion Concentration; Lymphoma; Male; Mice; Quantum Dots; Tellurium; Xanthones
PubMed: 27799767
DOI: 10.2147/IJN.S115037 -
Small (Weinheim An Der Bergstrasse,... Jan 2016Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as...
Many cancers show primary or acquired drug resistance due to the overexpression of efflux pumps. A novel mechanism to circumvent this is to integrate drugs, such as anthracycline antibiotics, with nanoparticle delivery vehicles that can bypass intrinsic tumor drug-resistance mechanisms. DNA nanoparticles serve as an efficient binding platform for intercalating drugs (e.g., anthracyclines doxorubicin and daunorubicin, which are widely used to treat acute leukemias) and enable precise structure design and chemical modifications, for example, for incorporating targeting capabilities. Here, DNA nanostructures are utilized to circumvent daunorubicin drug resistance at clinically relevant doses in a leukemia cell line model. The fabrication of a rod-like DNA origami drug carrier is reported that can be controllably loaded with daunorubicin. It is further directly verified that nanostructure-mediated daunorubicin delivery leads to increased drug entry and retention in cells relative to free daunorubicin at equal concentrations, which yields significantly enhanced drug efficacy. Our results indicate that DNA origami nanostructures can circumvent efflux-pump-mediated drug resistance in leukemia cells at clinically relevant drug concentrations and provide a robust DNA nanostructure design that could be implemented in a wide range of cellular applications due to its remarkably fast self-assembly (≈5 min) and excellent stability in cell culture conditions.
Topics: Animals; DNA Adducts; Daunorubicin; Doxorubicin; Drug Delivery Systems; Drug Resistance, Neoplasm; Endocytosis; HL-60 Cells; Horses; Humans; Intercalating Agents; Leukemia; Lysosomes; Models, Biological; Nanostructures; Nucleic Acid Conformation
PubMed: 26583570
DOI: 10.1002/smll.201502118 -
Postgraduate Medical Journal May 1970Daunorubicin has been used in the treatment of six cases of acute lymphoblastic and thirteen cases of acute myeloblastic and mono-myeloblastic leukaemia. Complete...
Daunorubicin has been used in the treatment of six cases of acute lymphoblastic and thirteen cases of acute myeloblastic and mono-myeloblastic leukaemia. Complete remissions were obtained in eight patients, three with acute lymphoblastic leukaemia and five with acute myeloblastic leukaemia. Marrow aplasia makes the drug difficult to administer, but no patients died from this cause, in this series. In some patients good remissions were obtained with relatively low doses of daunorubicin after preliminary treatment with 6-mercaptopurine.
Topics: Adolescent; Adult; Aged; Child; Daunorubicin; Female; Humans; Injections, Intravenous; Leukemia, Lymphoid; Leukemia, Myeloid, Acute; Male; Mercaptopurine; Middle Aged
PubMed: 5270679
DOI: 10.1136/pgmj.46.535.272 -
International Journal of Molecular... Oct 2022Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC),...
Daunorubicin (DNR) and cardiolipin (CL) were co-delivered using thermosensitive liposomes (TSLs). 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1-myristoyl-2-stearoyl-sn-glycero-3-phosphocholine (MSPC), cholesterol, 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000] or DSPE-mPEG (2000) and CL were used in the formulation of liposomes at a molar ratio of 57:40:30:3:20, respectively. CL forms raft-like microdomains that may relocate and change lipid organization of the outer and inner mitochondrial membranes. Such transbilayer lipid movement eventually leads to membrane permeabilization. TSLs were prepared by thin-film hydration (drug:lipid ratio 1:5) where DNR was encapsulated within the aqueous core of the liposomes and CL acted as a component of the lipid bilayer. The liposomes exhibited high drug encapsulation efficiency (>90%), small size (~115 nm), narrow size distribution (polydispersity index ~0.12), and a rapid release profile under the influence of mild hyperthermia. The liposomes also exhibited ~4-fold higher cytotoxicity against MDA-MB-231 cells compared to DNR or liposomes similar to DaunoXome® (p < 0.001). This study provides a basis for developing a co-delivery system of DNR and CL encapsulated in liposomes for treatment of breast cancer.
Topics: Breast Neoplasms; Cardiolipins; Cholesterol; Daunorubicin; Female; Humans; Lipid Bilayers; Liposomes; MCF-7 Cells; Phosphorylcholine; Polyethylene Glycols
PubMed: 36233061
DOI: 10.3390/ijms231911763 -
Biochimica Et Biophysica Acta.... Feb 2020The interactions of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA), with phospholipid monolayers used as simple models of cell membranes, were...
The influence of charge and lipophilicity of daunorubicin and idarubicin on their penetration of model biological membranes - Langmuir monolayer and electrochemical studies.
The interactions of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA), with phospholipid monolayers used as simple models of cell membranes, were investigated. The results of Langmuir experiments together with Brewster angle microscopy showed that both drugs strongly affect cancer cell membranes composed of 1,2-dimyristoyl-sn-glycero-3-phospho-l-serine (DMPS). Electrostatic interactions allow positively charged DNR and IDA to interact with negatively charged DMPS polar heads but increased lipophilicity of IDA allows it to penetrate the layer more effectively than DNR and prevents from its expulsion at higher surface pressures. The analysis of the thermodynamical functions of hysteresis proves the presence of the enthalpically favorable interactions within the monolayer during its compression in the presence of idarubicin, which may form aggregates with DMPS molecules. The influence of the drugs was significantly less pronounced for a healthy cell model composed of 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) due to the lack of strong electrostatic attractions. The interactions of drugs with pre-compressed phospholipid monolayers were also examined. The physical state of the monolayer and its packing determined only to some extent the penetration of anthracyclines. Since drug molecules first approach the polar region of the monolayer, the increase in surface pressure in time was more pronounced for negatively charged DMPS monolayers than for zwitterionic DMPC. Additionally, idarubicin was able to penetrate the precompressed DMPS monolayers more effectively than daunorubicin due to increased lipophilicity. This property of the drug was also responsible for IDA better penetration of hydrocarbon chains of supported DMPS monolayers compared to DNR, as shown by electrochemical studies.
Topics: Antineoplastic Agents; Cell Membrane; Daunorubicin; Dimyristoylphosphatidylcholine; Hydrophobic and Hydrophilic Interactions; Idarubicin; Static Electricity; Unilamellar Liposomes
PubMed: 31672546
DOI: 10.1016/j.bbamem.2019.183104 -
Cancer Chemotherapy and Pharmacology Nov 2016Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors,...
PURPOSE
Chemotherapy drug resistance and relapse of the disease have been the major factors limiting the success of acute myeloid leukemia (AML) therapy. Several factors, including the pharmacokinetics (PK) of Cytarabine (Ara-C) and Daunorubicin (Dnr), could contribute to difference in treatment outcome in AML.
METHODS
In the present study, we evaluated the plasma PK of Dnr, the influence of genetic polymorphisms of genes involved in transport and metabolism of Dnr on the PK, and also the influence of these factors on clinical outcome. Plasma levels of Dnr and its major metabolite, Daunorubicinol (DOL), were available in 70 adult de novo AML patients. PK parameters (Area under curve (AUC) and clearance (CL)) of Dnr and DOL were calculated using nonlinear mixed-effects modeling analysis performed with Monolix. Genetic variants in ABCB1, ABCG2, CBR1, and CBR3 genes as well as RNA expression of CBR1, ABCB1, and ABCG2 were compared with Dnr PK parameters.
RESULTS
The AUC and CL of Dnr and DOL showed wide inter-individual variation. Patients with an exon1 variant of rs25678 in CBR1 had significantly higher plasma Dnr AUC [p = 0.05] compared to patients with wild type. Patients who achieved complete remission (CR) had significantly lower plasma Dnr AUC, Cmax, and higher CL compared to patients who did not achieve CR.
CONCLUSION
Further validation of these findings in a larger cohort of AML patients is warranted before establishing a therapeutic window for plasma Dnr levels and targeted dose adjustment.
Topics: Adolescent; Adult; Alcohol Oxidoreductases; Antibiotics, Antineoplastic; Biotransformation; Daunorubicin; Drug Interactions; Female; Genetic Variation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Pharmacogenetics; Polymorphism, Genetic; Prospective Studies; Treatment Outcome; Young Adult
PubMed: 27738808
DOI: 10.1007/s00280-016-3166-8 -
Biomedicine & Pharmacotherapy =... Aug 2021Endometrial cancer (EC) is the most common neoplasm of the female reproductive tract in the developed world. Patients usually are diagnosed in early stage having a good...
Endometrial cancer (EC) is the most common neoplasm of the female reproductive tract in the developed world. Patients usually are diagnosed in early stage having a good prognosis. However, up to 20-25% of patients are diagnosed in advanced stages and have a higher risk of recurrence, making the prognosis worse. Previously studies identified ANXA2 as a predictor of recurrent disease in EC even in low risk patients. Furthermore, Circulating Tumor Cells (CTC) released from the primary tumor into the bloodstream, are plasticity entities responsible of the process of metastasis, becoming into an attractive clinical target. In this work we validated ANXA2 expression in CTC from high-risk EC patients. After that, we modelled in vitro and in vivo the tumor cell attachment of ANXA2-expressing CTC to the endothelium and the homing for the generation of micrometastasis. ANXA2 overexpression does not provide an advantage in the adhesion process of CTC, but it could be playing an important role in more advanced steps, conferring a greater homing capacity. We also performed a high-throughput screening (HTS) for compounds specifically targeting ANXA2, and selected Daunorubicin as candidate hit. Finally, we validated Daunorubicin in a 3D transendothelial migration system and also in a in vivo model of advanced EC, demonstrating the ability of Daunorubicin to inhibit the proliferation of ANXA2-overexpressing tumor cells.
Topics: Animals; Annexin A2; Cell Adhesion; Cell Line; Cell Movement; Cell Proliferation; Daunorubicin; Endometrial Neoplasms; Endothelium; Female; High-Throughput Screening Assays; Humans; Liquid Biopsy; Mice; Models, Biological; Neoplastic Cells, Circulating
PubMed: 34049223
DOI: 10.1016/j.biopha.2021.111744 -
Biomedicine & Pharmacotherapy =... Sep 2022Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar...
Lysosomes, now known to take part in multiple cellular functions, also respond to various stress stimuli. These include biogenesis in response to nanomolar concentrations of hydrophobic weak-base anticancer drugs. However, since lysosomal stress mediated by accumulation of weak-base drugs at such concentrations has never been proven and these drugs have diverse effects on malignant cells, we investigated whether the interpretation of the data was true. We found that lysosomal accumulation of the drugs daunorubicin, doxorubicin, mitoxantrone, symadex, chloroquine, clomipramine and sunitinib alone, was insufficient to induce lysosomal alkalization i.e., lysosomal stress-mediated biogenesis at nanomolar concentrations. Instead, we found that some of the drugs used induced G2 phase arrest and lysosomal biogenesis that is associated with activation of transcription factor EB (TFEB). Similarly, cantharidin, a control compound that does not belong to the weak base drugs, induced cell cycle arrest in the G2 phase associated with TFEB-driven lysosomal biogenesis. Overall none of the tested drugs caused stress-induced lysosomal biogenesis at nanomolar concentrations. However, daunorubicin, doxorubicin, mitoxantrone, symadex and cantharidin induced a massive block in the G2 phase of the cell cycle which is naturally associated with TFEB-driven lysosomal biogenesis.
Topics: Autophagy; Cantharidin; Cell Cycle; Doxorubicin; Lysosomes; Mitoxantrone
PubMed: 35785701
DOI: 10.1016/j.biopha.2022.113328