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Spectrochimica Acta. Part A, Molecular... Jul 2023Chemotherapy-phototherapy (CTPT) combination drugs co-loaded by targeted DNA nanostructures can achieve controlled drug delivery, reduce toxic side effects and overcome...
Chemotherapy-phototherapy (CTPT) combination drugs co-loaded by targeted DNA nanostructures can achieve controlled drug delivery, reduce toxic side effects and overcome multidrug resistance. Herein, we constructed and characterized a DNA tetrahedral nanostructure (MUC1-TD) linked with the targeting aptamer MUC1. The interaction of daunorubicin (DAU)/acridine orange (AO) alone and in combination with MUC1-TD and the influence of the interaction on the cytotoxicity of the drugs were evaluated. Potassium ferrocyanide quenching analysis and DNA melting temperature assays were used to demonstrate the intercalative binding of DAU/AO to MUC1-TD. The interactions of DAU and/or AO with MUC1-TD were analyzed by fluorescence spectroscopy and differential scanning calorimetry. The number of binding sites, binding constant, entropy and enthalpy changes of the binding process were obtained. The binding strength and binding sites of DAU were higher than those of AO. The presence of AO in the ternary system weakened the binding of DAU to MUC1-TD. In vitro cytotoxicity studies demonstrated that the loading of MUC1-TD augmented the inhibitory effects of DAU and AO and the synergistic cytotoxic effects of DAU + AO on MCF-7 cells and MCF-7/ADR cells. Cell uptake studies showed that the loading of MUC1-TD was beneficial in promoting the apoptosis of MCF-7/ADR cells due to its enhanced targeting to the nucleus. This study has important guiding significance for the combined application of DAU and AO co-loaded by DNA nanostructures to overcome multidrug resistance.
Topics: Daunorubicin; Acridine Orange; Antineoplastic Agents; Drug Delivery Systems; DNA
PubMed: 36905740
DOI: 10.1016/j.saa.2023.122583 -
Investigational New Drugs Oct 2023Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances...
Approximately 60%-80% of patients who achieve complete remission eventually relapse after conventional chemotherapy and have poor prognoses despite the recent advances of novel anticancer agents. Continuing development of more effective novel treatments for acute myeloid leukemia (AML) is necessary. We developed (R)-WAC-224 (R-WAC), which is an anticancer quinolone, targeting topoisomerase II. This study evaluated the anti-leukemia potential of R-WAC or racemic WAC-224 (WAC) in vitro and in vivo. R-WAC significantly inhibited the human AML cell line proliferation (MV4-11, HL60, and KG1a), which was comparable to daunorubicin and cytarabine, not affected by P-glycoprotein overexpression. WAC did neither increase serum troponin-T nor decrease the crypt numbers in the small intestine, indicating WAC was less toxic than doxorubicin. R-WAC monotherapy demonstrated prolonged survival in the AML mice model and inhibited tumor growth in the MV4-11 xenograft mice model. Moreover, the combination of R-WAC and cytarabine demonstrated more active anti-leukemia effects than daunorubicin and cytarabine. Finally, R-WAC inhibited the colony-forming abilities using primary AML cells. These results indicate that R-WAC is a promising therapeutic agent for AML.
Topics: Humans; Animals; Mice; Quinolones; Drug Synergism; Leukemia, Myeloid, Acute; Daunorubicin; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Adaptor Proteins, Signal Transducing
PubMed: 37702844
DOI: 10.1007/s10637-023-01393-0 -
Tumori Jun 2016In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a... (Review)
Review
In May 1960, the Farmitalia CEO Dr. Bertini and the director of the Istituto Nazionale dei Tumori of Milan Prof. Bucalossi (talent scout and city's Mayor) signed a research agreement for the discovery and development up to clinical trials of new natural antitumor agents. This agreement can be considered as a pioneering and fruitful example of a translational discovery program with relevant transatlantic connections. Owing to an eclectic Streptomyces, found near Castel del Monte (Apulia), and to the skilled and motivated participants of both institutions, a new natural antitumor drug, daunomycin, was ready for clinical trials within 3 years. Patent interference by the Farmitalia French partner was overcome by the good quality of the Italian drug and by the cooperation between Prof. Di Marco, director of the Istituto Ricerche Farmitalia Research Laboratories for Microbiology and Chemotherapy, and Prof. Karnofsky, head of the Sloan-Kettering Cancer Institute of New York, leading to the first transatlantic clinical trials. The search for daunomycin's sister anthracyclines led to the discovery and development of adriamycin, one of the best drugs born in Milan. This was the second act prologue of the history of Italian antitumor discovery and clinical oncology, which started in July 1969 when Prof. Di Marco sent Prof. Bonadonna the first vials of adriamycin (doxorubicin) to be tested in clinical trials. This article reviews the Milan scene in the 1960s, a city admired and noted for the outstanding scientific achievements of its private and public institutions in drugs and industrial product discovery.
Topics: Academies and Institutes; Anthracyclines; Antibiotics, Antineoplastic; Clinical Trials as Topic; Daunorubicin; Doxorubicin; Drug Approval; Drug Discovery; Drug Industry; France; History, 20th Century; History, 21st Century; Humans; Interdisciplinary Communication; Italy; Medical Oncology; Neoplasms; Patents as Topic; Public-Private Sector Partnerships; Streptomyces; Translational Research, Biomedical; United States
PubMed: 27103205
DOI: 10.5301/tj.5000507 -
Colloids and Surfaces. B, Biointerfaces Sep 2022Various studies were performed on the intermolecular interactions of daunorubicin (DNR) and cytarabine (Ara-C) co-loaded liposome to predict and elucidate its stability...
Various studies were performed on the intermolecular interactions of daunorubicin (DNR) and cytarabine (Ara-C) co-loaded liposome to predict and elucidate its stability and in vitro drug release behavior. Langmuir monolayer and spectroscopy studies showed interactions between its components. The Langmuir monolayer study and blank liposomes stability study illustrated that interactions between lipids could affect their stability, and the DSPC/DSPG/Chol (7/2/1, mol%) mixed system tended to be thermodynamically and physicochemically stable. The interactions between daunorubicin and copper ions were then investigated by ultraviolet-visible (UV-vis) electronic absorption spectroscopy and circular dichroism (CD) spectroscopy, which revealed that the DNR-Cu complex was composed of daunorubicin and copper ions at a molar ratio of 1:1 or 1:2, and its solubility was related to the acidity of the solution. In vitro release experiment of liposomes with different copper gluconate contents illustrated that the interactions between drugs and copper ions were conducive to the retention and synergetic release of drugs. The stability and release studies of the DSPC/DSPG/Chol (7/2/1, mol%) co-loaded liposome illustrated that it had good storage and plasma stability, and the release behaviors of drugs were pH-related, i.e., drugs could be released faster under acidic condition. These studies indicated that intermolecular interactions could affect the stability and release behavior of the liposome, and a certain ratio of components could be conducive to its stability and synergistic release of drugs.
Topics: Copper; Cytarabine; Daunorubicin; Drug Liberation; Drug Stability; Liposomes
PubMed: 35780612
DOI: 10.1016/j.colsurfb.2022.112673 -
Toxicology in Vitro : An International... Apr 2015Although anthracycline antibiotics have been successfully used for nearly half a century in the treatment of various malignancies, their use is limited by their cardiac... (Comparative Study)
Comparative Study
Although anthracycline antibiotics have been successfully used for nearly half a century in the treatment of various malignancies, their use is limited by their cardiac and vascular toxicities, and the mechanisms of these toxicities are still not entirely clear. Herein, we comprehensively characterized cytotoxic effects of two structurally related anthracyclines, doxorubicin and daunorubicin. In nanomolar concentrations, both drugs induced DNA damage and increased nuclear area that were associated with their accumulation in the nucleus (doxorubicin ⩾50 nM and daunorubicin ⩾25 nM) as evidence by Raman microspectroscopy at 3820-4245 cm(-1). At low micromolar concentrations, doxorubicin (⩾5 μM) and daunorubicin (⩾1 μM) increased the generation of reactive oxygen species, decreased intracellular reduced glutathione, induced an alteration in endothelial elasticity and caused a reorganization of the F-actin cytoskeleton. In isolated mouse aortic rings, doxorubicin (⩾50 μM) was less potent than daunorubicin (⩾5 μM) in impairing the endothelium-dependent response. In summary, using a comprehensive endothelial profiling approach, we demonstrated clear-cut differences in the potencies to induce endotheliotoxic responses for two structurally similar chemotherapeutics, at a nuclear, cytosolic and membrane levels. Furthermore, our results suggest that the differences in the endothelial toxicities of doxorubicin and daunorubicin are linked to differences in their nuclear accumulation and the DNA damage-triggered response of the endothelium.
Topics: Actins; Animals; Antibiotics, Antineoplastic; Aorta, Thoracic; Caspases; Cell Line; Cell Survival; Cells, Cultured; Daunorubicin; Doxorubicin; Endothelial Cells; High-Throughput Screening Assays; In Vitro Techniques; Mice; Reactive Oxygen Species
PubMed: 25529801
DOI: 10.1016/j.tiv.2014.12.009 -
Molecular Medicine Reports Jul 2017Despite advances in the treatment of T‑cell acute lymphoblastic leukemia (T‑ALL), the outcome of T‑ALL treatment remains unsatisfactory, therefore, more effective...
Despite advances in the treatment of T‑cell acute lymphoblastic leukemia (T‑ALL), the outcome of T‑ALL treatment remains unsatisfactory, therefore, more effective treatment is urgently required. The present study examined the cytotoxicities of bortezomib in combination with daunorubicin against human Jurkat and Molt‑4 T‑ALL cells and primary T‑ALL cells. Compared with treatment alone, co‑exposure of cells to bortezomib and daunorubicin resulted in a significant increase in cell death in the Jurkat cells, as evidenced by the increased percentage of Annexin V‑positive cells, the formation of apoptotic bodies. In addition, the administration sequence of bortezomib and daunorubicin had an effect on cell viability. Treatment with bortezomib followed by daunorubicin treatment was more effective, compared with treatment with daunorubicin followed by bortezomib. Co-treatment with bortezomib and daunorubicin markedly enhanced the activation of caspase‑3, ‑8 and ‑9, which was reversed by the pan‑caspase inhibitor, Z‑VAD‑FMK. In addition, cotreatment with bortezomib and daunorubicin enhanced the collapse of mitochondrial transmembrane potential and upregulated the proapoptotic protein, B‑cell lymphoma 2 (Bcl‑2)‑interacting mediator of cell death (Bim), but not Bcl‑2 or Bcl‑extra large. Consistent with this, it was demonstrated that cotreatment of bortezomib and daunorubicin efficiently induced apoptosis in primary T‑ALL cells, and cell death was associated with the collapse of mitochondrial transmembrane potential and the upregulation of Bim. Taken together, these findings indicated that the combination of bortezomib and daunorubicin significantly enhanced their apoptosis‑inducing effect in T‑ALL cells, which may warrant further investigation in preclinical and clinical investigations.
Topics: Antineoplastic Agents; Apoptosis; Bcl-2-Like Protein 11; Bortezomib; Caspases; Cell Line, Tumor; Cell Proliferation; Cell Survival; Daunorubicin; Drug Synergism; Gene Expression; Humans; Jurkat Cells; Membrane Potential, Mitochondrial; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 28487980
DOI: 10.3892/mmr.2017.6554 -
Current Medicinal Chemistry 2019Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite... (Review)
Review
Acute Myeloid Leukaemia (AML) is the neoplastic transformation of Hematopoietic Stem Cells (HSC) and relapsed disease is a major challenge in the treatment. Despite technological advances in the field of medicine and our heightened knowledge regarding the pathogenesis of AML, the initial therapy of "7+3" Cytarabine and Daunorubicin has remained mainly unchanged since 1973. AML is a disease of the elderly, and increased morbidity in this patient group does not allow the full use of the treatment and drug-resistant relapse is common. Nanocarriers are drug-delivery systems that can be used to transport drugs to the bone marrow and target Leukemic Stem Cells (LSC), conferring less side-effects compared to the free-drug alternative. Nanocarriers also can be used to favour the transport of drugs that otherwise would not have been used clinically due to toxicity and poor efficacy. Liposomes are a type of nanocarrier that can be used as a dedicated drug delivery system, which can also have active ligands on the surface in order to interact with antigens on the target cells or tissues. In addition to using small molecules, it is possible to attach antibodies to the liposome surface, generating so-called immunoliposomes. By using immunoliposomes as a drug-delivery system, it is possible to minimize the toxic side effects caused by the chemotherapeutic drug on healthy organs, and at the same time direct the drugs towards the remaining AML blasts and stem cells. This article aims to explore the possibilities of using immunoliposomes as a drug carrier in AML therapy. Emphasis will be on possible target molecules on the AML cells, leukaemic stem cells, as well as bone marrow constituents relevant to AML therapy. Further, some conditions and precautions that must be met for immunoliposomes to be used in AML therapy will be discussed.
Topics: Animals; Antineoplastic Agents; Cytarabine; Daunorubicin; Drug Carriers; Drug Screening Assays, Antitumor; Humans; Leukemia, Myeloid, Acute; Liposomes; Nanoparticles
PubMed: 31099318
DOI: 10.2174/0929867326666190517114450 -
Bioscience Reports Apr 2020Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about...
Tripartite motif (TRIM) 31 is a member of TRIM family and exerts oncogenic role in the progression and drug resistance of several cancers. However, little is known about the relevance of TRIM31 in acute myeloid leukemia (AML). Herein, we investigated the role of TRIM31 in AML. We examined the expression levels of TRIM31 in the blood samples from 34 patients with AML and 34 healthy volunteers using qRT-PCR. The mRNA levels of TRIM31 in human bone marrow stromal cells (HS-5) and five AML cell lines were also detected. Loss/gain-of-function assays were performed to assess the role of TRIM31 in AML cells proliferation, apoptosis and sensitivity to daunorubicin. The expression levels of pro-caspase 3, cleaved caspase 3, Wnt3a, β-catenin, cyclin D1 and c-Myc were measured using Western blot. TRIM31 expression levels were significantly up-regulated in AML patients and cell lines. Knockdown of TRIM31 suppressed cell proliferation and promoted apoptosis in AML-5 and U937 cells. The IC50 of daunorubicin was significantly decreased in TRIM31 siRNA (si-TRIM31) transfected cells. Oppositely, induced cell proliferation and decreased cell apoptosis were observed in pcDNA-3.1-TRIM31 transfected cells. Furthermore, knockdown of TRIM31 suppressed the activation of Wnt/β-catenin pathway in AML cells. Activation of Wnt/β-catenin pathway by LiCl abolished the effects of si-TRIM31 on cell proliferation, apoptosis and sensitivity to daunorubicin in AML cells. In conclusion, the results indicated that TRIM31 promoted leukemogenesis and chemoresistance to daunorubicin in AML. The oncogenic role of TRIM31 in AML was mediated by the Wnt/β-catenin pathway. Thus, TRIM31 might serve as a therapeutic target for the AML treatment.
Topics: Antibiotics, Antineoplastic; Apoptosis; Case-Control Studies; Cell Line, Tumor; Cell Proliferation; Daunorubicin; Disease Progression; Drug Resistance, Neoplasm; Healthy Volunteers; Humans; Leukemia, Myeloid, Acute; Lithium Chloride; RNA, Small Interfering; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Wnt Signaling Pathway
PubMed: 32232394
DOI: 10.1042/BSR20194334 -
Cancer Chemotherapy and Pharmacology Oct 2014We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
PURPOSE
We explored the impact of obesity, body composition, and genetic polymorphisms on the pharmacokinetics (PK) of daunorubicin in children with cancer.
PATIENTS AND METHODS
Patients ≤21 years receiving daunorubicin as an infusion of any duration <24 h for any type of cancer were eligible. Plasma drug concentrations were measured by high-performance liquid chromatography. Body composition was measured by dual-energy X-ray absorptiometry. Obesity was defined as a BMI >95% for age or as body fat >30%. NONMEM was used to perform PK model fitting. The Affymetrix DMET chip was used for genotyping. The impact of genetic polymorphisms was investigated using SNP/haplotype association analysis with estimated individual PK parameters.
RESULTS
A total of 107 subjects were enrolled, 98 patients had PK sampling, and 50 patients underwent DNA analysis. Population estimates for daunorubicin clearance and volume of distribution were 116 L/m(2)/h ± 14% and 68.1 L/m(2) ± 24%, respectively. Apparent daunorubicinol clearance and volume of distribution were 26.8 L/m(2)/h ± 5.6% and 232 L/m(2) ± 10%, respectively. No effect of body composition or obesity was observed on PK. Forty-four genes with variant haplotypes were tested for association with PK. FMO3-H1/H3 genotype was associated with lower daunorubicin clearance than FMO3-H1/H1, p = 0.00829. GSTP1*B/*B genotype was also associated with lower daunorubicin clearance compared to GSTP1*A/*A, p = 0.0347. However, neither of these associations was significant after adjusting for multiple testing by either Bonferroni or false discovery rate correction.
CONCLUSIONS
We did not detect an effect of body composition or obesity on daunorubicin PK. We found suggestive associations between FMO3 and GSTP1 haplotypes with daunorubicin PK that could potentially affect efficacy and toxicity.
Topics: Absorptiometry, Photon; Antibiotics, Antineoplastic; Body Composition; Body Mass Index; Child; Daunorubicin; Drug Screening Assays, Antitumor; Female; Genome-Wide Association Study; Glutathione S-Transferase pi; Haplotypes; Humans; Male; Metabolic Clearance Rate; Models, Statistical; Neoplasms; Obesity; Oxygenases; Pharmacogenetics; Polymorphism, Genetic
PubMed: 25119182
DOI: 10.1007/s00280-014-2535-4 -
International Journal of Biological... Nov 2023The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In...
The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In this study, we designed an antisense oligonucleotides (ASOs)-linked DNA tetrahedron (ASOs-TD). The detection limit of ASOs-TD for MDR1 mRNA was 0.05 μM. By using fluorescence spectroscopy and isothermal titration calorimetry (ITC), the interactions between doxorubicin (DOX) /daunorubicin (DAU) and ASOs-TD were investigated. The number of binding sites (n), binding constant (K), entropy change (ΔS), enthalpy change (ΔH) and Gibbs free energy change (ΔG) were obtained. The intercalation of DOX/DAU with ASOs-TD was demonstrated by differential scanning calorimetry (DSC) and quenching researches of potassium ferricyanide K[Fe(CN)]. The in vitro release rate of DOX/DAU loaded in ASOs-TD was accelerated by deoxyribonuclease I (DNase I). In vitro cytotoxicity proved the good gene therapy effect of ASOs-TD and the increased cytotoxicity of DOX/DAU to MCF-7/ADR cells. The results of confocal laser scanning microscope (CLSM) suggested that ASOs-TD could effectively identify drug-resistant cells due to its good imaging ability for MDR1 mRNA. This work offers theoretical significance for overcoming MDR using DNA nanostructures which combine diagnostic imaging, chemotherapy, and gene therapy.
Topics: Doxorubicin; Humans; Thermodynamics; DNA; Genetic Therapy; Daunorubicin; MCF-7 Cells; Drug Carriers; Oligonucleotides, Antisense
PubMed: 37562474
DOI: 10.1016/j.ijbiomac.2023.126245