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International Journal of Molecular... Aug 2022To endow the polymeric prodrug with smart properties through a safe and simple method, matrix metalloproteinase (MMPs) responsive peptide GPLGVRGDG was introduced into...
To endow the polymeric prodrug with smart properties through a safe and simple method, matrix metalloproteinase (MMPs) responsive peptide GPLGVRGDG was introduced into the block copolymer to prepare TPGS-GPLGVRGDG-DOX&DOX micelles, where TPGS is D-α-tocopheryl polyethylene glycol 3350 succinate. During the doxorubicin delivery, the cleavage of the peptide chain triggers de-PEGylation, and the remaining VRGDG sequence was retained on the surface of the micelles, which can act as a ligand to facilitate cell uptake. Moreover, the cytotoxicity of TPGS-GPLGVRGDG-DOX&DOX micelles against 4T1 cells was significantly improved, compared with TPGS-GPLGVRG-DOX&DOX micelles and TPGS-DOX&DOX micelles. During in vivo studies, TPGS-GPLGVRGDG-DOX&DOX micelles exhibited good anticancer efficacy with long circulation in the body and more efficient accumulation at the tumor site. Therefore, TPGS-GPLGVRGDG-DOX&DOX micelles have improved antitumor activity and reduced toxic side effects. This work opens new potential for exploring the strategy of drug delivery in clinical applications.
Topics: Cell Line, Tumor; Doxorubicin; Drug Carriers; Drug Delivery Systems; Micelles; Peptides; Polyethylene Glycols; Polymers
PubMed: 36077102
DOI: 10.3390/ijms23179698 -
Scientific Reports Jan 2020Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in...
Unexpectedly, the widely used anticancer agents Cisplatin (Cis-Pt) and Daunorubicin (Dauno) exhibited cell type- and concentration-dependent synergy or antagonism in vitro. We attempted to interpret these effects in terms of the changes elicited by the drugs in the chromatin, the target held primarily responsible for the cytotoxicity of both agents. We measured the effect of Cis-Pt on the levels of Dauno in different cell compartments, the effect of Cis-Pt on Dauno-induced nucleosome eviction, and assessed the influence of Dauno on DNA platination in flow- and laser scanning cytometry as well as in laser ablation-inductively coupled plasma-mass spectrometry assays. We show that the two drugs antagonize each other through a decrease of interstrand crosslinks upon co-treatment with Dauno, and also via the diminished Dauno uptake in the presence of Cis-Pt, and both effects are observed already at low Dauno concentrations. At high Dauno concentrations synergy becomes dominant because histone eviction by Dauno intercalation into the DNA is enhanced in the presence of co-treatment with Cis-Pt. These interactions may have an impact on the efficacy of combination treatment protocols, considering the long retention time of DNA adducts formed by both agents.
Topics: Antineoplastic Agents; Cell Line, Tumor; Chromatin; Cisplatin; DNA Adducts; DNA, Neoplasm; Daunorubicin; Dose-Response Relationship, Drug; Drug Interactions; Humans
PubMed: 31980698
DOI: 10.1038/s41598-020-57702-7 -
International Journal of Oncology Jun 2024Daunorubicin, also known as daunomycin, is a DNA‑targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to...
Daunorubicin, also known as daunomycin, is a DNA‑targeting anticancer drug that is used as chemotherapy, mainly for patients with leukemia. It has also been shown to have anticancer effects in monotherapy or combination therapy in solid tumors, but at present it has not been adequately studied in colorectal cancer (CRC). In the present study, from a screening using an FDA‑approved drug library, it was found that daunorubicin suppresses GLI‑dependent luciferase reporter activity. Daunorubicin also increased p53 levels, which contributed to both GLI1 suppression and apoptosis. The current detailed investigation showed that daunorubicin promoted the β‑TrCP‑mediated ubiquitination and proteasomal degradation of GLI1. Moreover, a competition experiment using BODIPY‑cyclopamine, a well‑known Smo inhibitor, suggested that daunorubicin does not bind to Smo in HCT116 cells. Administration of daunorubicin (2 mg/kg, ip, qod, 15 days) into HCT116 xenograft mice profoundly suppressed tumor progress and the GLI1 level in tumor tissues. Taken together, the present results revealed that daunorubicin suppresses canonical Hedgehog pathways in CRC. Ultimately, the present study discloses a new mechanism of daunorubicin's anticancer effect and might provide a rationale for expanding the clinical application of daunorubicin.
Topics: Humans; Zinc Finger Protein GLI1; Daunorubicin; Colorectal Neoplasms; Animals; Mice; Apoptosis; Xenograft Model Antitumor Assays; HCT116 Cells; Smoothened Receptor; Antibiotics, Antineoplastic; Signal Transduction; Gene Expression Regulation, Neoplastic; Ubiquitination; Cell Line, Tumor; Cell Proliferation
PubMed: 38757343
DOI: 10.3892/ijo.2024.5654 -
Haematologica Nov 2022Resistance to chemotherapeutic drugs is a major cause of treatment failure in acute myeloid leukemias (AML). To better characterize the mechanisms of chemoresistance, we...
Resistance to chemotherapeutic drugs is a major cause of treatment failure in acute myeloid leukemias (AML). To better characterize the mechanisms of chemoresistance, we first identified genes whose expression is dysregulated in AML cells resistant to daunorubicin or cytarabine, the main drugs used for induction therapy. The genes found to be activated are mostly linked to immune signaling and inflammation. Among them, we identified a strong upregulation of the NOX2 NAPDH oxidase subunit genes (CYBB, CYBA, NCF1, NCF2, NCF4 and RAC2). The ensuing increase in NADPH oxidase expression and production of reactive oxygen species, which is particularly strong in daunorubicin-resistant cells, participates in the acquisition and/or maintenance of resistance to daunorubicin. Gp91phox (CYBB-encoded Nox2 catalytic subunit), was found to be more expressed and active in leukemic cells from patients with the French-American-British (FAB) M4/M5 subtypes of AML than in those from patients with the FAB M0-M2 ones. Moreover, its expression was increased at the surface of patients' chemotherapy-resistant AML cells. Finally, using a gene expression based score we demonstrated that high expression of NOX2 subunit genes is a marker of adverse prognosis in AML patients. The prognostic NOX score we defined is independent of the cytogenetic-based risk classification, FAB subtype, FLT3/NPM1 mutational status and age.
Topics: Humans; Daunorubicin; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute; Prognosis; NADPH Oxidase 2
PubMed: 35172562
DOI: 10.3324/haematol.2021.279889 -
International Journal of Molecular... Dec 2022Chemoresistance is one of the major challenges for the treatment of acute myeloid leukemia. Epigallocatechin gallate (EGCG), a bioactive polyphenol from green tea, has...
Chemoresistance is one of the major challenges for the treatment of acute myeloid leukemia. Epigallocatechin gallate (EGCG), a bioactive polyphenol from green tea, has attracted immense interest as a potential chemosensitizer, but its application is limited due to the need for effective formulations capable of co-delivering EGCG and anti-leukemic drugs. Herein, we describe the formation and characterization of a micellar nanocomplex self-assembled from EGCG and daunorubicin, an anthracycline drug for the first-line treatment of acute myeloid leukemia. This nanocomplex was highly stable at pH 7.4 but stimulated to release the incorporated daunorubicin at pH 5.5, mimicking an acidic endosomal environment. More importantly, the nanocomplex exhibited superior cytotoxic efficacy against multidrug-resistant human leukemia cells over free daunorubicin by achieving a strong synergism, as supported by median-effect plot analysis. The observed chemosensitizing effect was in association with enhanced nucleus accumulation of daunorubicin, elevation of intracellular reactive oxygen species and caspase-mediated apoptosis induction. Our study presents a promising strategy for circumventing chemoresistance for more effective leukemia therapy.
Topics: Humans; Daunorubicin; Apoptosis; Drug Resistance, Neoplasm; Leukemia, Myeloid, Acute; Catechin; Tea
PubMed: 36613821
DOI: 10.3390/ijms24010381 -
Biosensors May 2023Doxorubicin (DOX) is widely used in chemotherapy as an anti-tumor drug. However, DOX is highly cardio-, neuro- and cytotoxic. For this reason, the continuous monitoring...
Doxorubicin (DOX) is widely used in chemotherapy as an anti-tumor drug. However, DOX is highly cardio-, neuro- and cytotoxic. For this reason, the continuous monitoring of DOX concentrations in biofluids and tissues is important. Most methods for the determination of DOX concentrations are complex and costly, and are designed to determine pure DOX. The purpose of this work is to demonstrate the capabilities of analytical nanosensors based on the quenching of the fluorescence of alloyed CdZnSeS/ZnS quantum dots (QDs) for operative DOX detection. To maximize the nanosensor quenching efficiency, the spectral features of QDs and DOX were carefully studied, and the complex nature of QD fluorescence quenching in the presence of DOX was shown. Using optimized conditions, turn-off fluorescence nanosensors for direct DOX determination in undiluted human plasma were developed. A DOX concentration of 0.5 µM in plasma was reflected in a decrease in the fluorescence intensity of QDs, stabilized with thioglycolic and 3-mercaptopropionic acids, for 5.8 and 4.4 %, respectively. The calculated Limit of Detection values were 0.08 and 0.03 μg/mL using QDs, stabilized with thioglycolic and 3-mercaptopropionic acids, respectively.
Topics: Humans; Alloys; Doxorubicin; Sulfides; Zinc Compounds
PubMed: 37366961
DOI: 10.3390/bios13060596 -
ELife Dec 2022Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II...
Anthracyclines are among the most used and effective anticancer drugs. Their activity has been attributed to DNA double-strand breaks resulting from topoisomerase II poisoning and to eviction of histones from select sites in the genome. Here, we show that the extensively used anthracyclines Doxorubicin, Daunorubicin, and Epirubicin decrease the transcription of nuclear factor kappa B (NF-κB)-dependent gene targets, but not interferon-responsive genes in primary mouse () macrophages. Using an NMR-based structural approach, we demonstrate that anthracyclines disturb the complexes formed between the NF-κB subunit RelA and its DNA-binding sites. The anthracycline variants Aclarubicin, Doxorubicinone, and the newly developed Dimethyl-doxorubicin, which share anticancer properties with the other anthracyclines but do not induce DNA damage, also suppressed inflammation, thus uncoupling DNA damage from the effects on inflammation. These findings have implications for anticancer therapy and for the development of novel anti-inflammatory drugs with limited side effects for life-threatening conditions such as sepsis.
Topics: Animals; Mice; Anthracyclines; NF-kappa B; Antibiotics, Antineoplastic; Doxorubicin; DNA Damage; DNA
PubMed: 36476511
DOI: 10.7554/eLife.77443 -
International Journal of Molecular... Aug 2023Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia...
Unlike genomic alterations, gene expression profiles have not been widely used to refine cancer therapies. We analyzed transcriptional changes in acute myeloid leukemia (AML) cell lines in response to standard first-line AML drugs cytarabine and daunorubicin by means of RNA sequencing. Those changes were highly cell- and treatment-specific. By comparing the changes unique to treatment-sensitive and treatment-resistant AML cells, we enriched for treatment-relevant genes. Those genes were associated with drug response-specific pathways, including calcium ion-dependent exocytosis and chromatin remodeling. Pharmacological mimicking of those changes using EGFR and MEK inhibitors enhanced the response to daunorubicin with minimum standalone cytotoxicity. The synergistic response was observed even in the cell lines beyond those used for the discovery, including a primary AML sample. Additionally, publicly available cytotoxicity data confirmed the synergistic effect of EGFR inhibitors in combination with daunorubicin in all 60 investigated cancer cell lines. In conclusion, we demonstrate the utility of treatment-evoked gene expression changes to formulate rational drug combinations. This approach could improve the standard AML therapy, especially in older patients.
Topics: Humans; Aged; Leukemia, Myeloid, Acute; Daunorubicin; Cell Line; Chromatin Assembly and Disassembly; ErbB Receptors
PubMed: 37629110
DOI: 10.3390/ijms241612926 -
Drug Delivery Dec 2022The present work aims to prove the concept of tumor-targeted drug delivery mediated by platelets. Doxorubicin (DOX) attached to nanodiamonds (ND-DOX) was investigated as...
The present work aims to prove the concept of tumor-targeted drug delivery mediated by platelets. Doxorubicin (DOX) attached to nanodiamonds (ND-DOX) was investigated as the model payload drug of platelets. In vitro experiments first showed that ND-DOX could be loaded in mouse platelets in a dose-dependent manner with a markedly higher efficiency and capacity than free DOX. ND-DOX-loaded platelets (Plt@ND-DOX) maintained viability and ND-DOX could be stably held in the platelets for at least 4 hr. Next, mouse Lewis lung cancer cells were found to activate Plt@ND-DOX and thereby stimulate cargo unloading of Plt@ND-DOX. The unloaded ND-DOX was taken up by co-cultured cancer cells which consequently exhibited loss of viability, proliferation suppression and apoptosis. In vivo, Plt@ND-DOX displayed significantly prolonged blood circulation time over ND-DOX and DOX in mice, and Lewis tumor grafts demonstrated infiltration, activation and cargo unloading of Plt@ND-DOX in the tumor tissue. Consequently, Plt@ND-DOX effectively reversed the growth of Lewis tumor grafts which exhibited significant inhibition of cell proliferation and apoptosis. Importantly, Plt@ND-DOX displayed a markedly higher therapeutic potency than free DOX but without the severe systemic toxicity associated with DOX. Our findings are concrete proof of platelets as efficient and efficacious carriers for tumor-targeted nano-drug delivery with the following features: 1) large loading capacity and high loading efficiency, 2) good tolerance of cargo drug, 3) stable cargo retention and no cargo unloading in the absence of stimulation, 4) prolonged blood circulation time, and 5) excellent tumor distribution and tumor-activated drug unloading leading to high therapeutic potency and few adverse effects. Platelets hold great potential as efficient and efficacious carriers for tumor-targeted nano-drug delivery.
Topics: Animals; Blood Platelets; Cell Survival; Doxorubicin; Mice; Nanodiamonds; Neoplasms
PubMed: 35319321
DOI: 10.1080/10717544.2022.2053762 -
The Oncologist Sep 2020On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal... (Review)
Review
EMA Review of Daunorubicin and Cytarabine Encapsulated in Liposomes (Vyxeos, CPX-351) for the Treatment of Adults with Newly Diagnosed, Therapy-Related Acute Myeloid Leukemia or Acute Myeloid Leukemia with Myelodysplasia-Related Changes.
On June 28, 2018, the Committee for Medicinal Products for Human Use adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Vyxeos, intended for the treatment of acute myeloid leukemia (AML). Vyxeos was designated as an orphan medicinal product on January 11, 2012. The applicant for this medicinal product was Jazz Pharmaceuticals Ireland Limited. Vyxeos is a liposomal formulation of a fixed combination of daunorubicin and cytarabine, antineoplastic agents that inhibit topoisomerase II activity and also cause DNA damage. The strength of Vyxeos is 5 units/mL, where 1 unit equals 1.0 mg cytarabine plus 0.44 mg daunorubicin. The marketing authorization holder Jazz Pharmaceuticals had found that this was an optimal ratio for the efficacy of the product. Study CLTR0310-301, a phase III, multicenter, randomized, trial of Vyxeos (daunorubicin-cytarabine) liposome injection versus standard 3+7 daunorubicin and cytarabine in patients aged 60-75 years with untreated high-risk (secondary) AML, showed a statistically significant difference between the two groups in overall survival (OS) with a median OS of 9.56 months in the daunorubicin-cytarabine arm compared with 5.95 months for standard chemotherapy (hazard ratio, 0.69; 95% confidence interval, 0.52-0.90; one-sided p = .003). The most common side effects were hypersensitivity including rash, febrile neutropenia, edema, diarrhea/colitis, mucositis, fatigue, musculoskeletal pain, abdominal pain, decreased appetite, cough, headache, chills, arrhythmia, pyrexia, sleep disorders, and hypotension. IMPLICATIONS FOR PRACTICE: Vyxeos has demonstrated a clinically significant improvement in overall survival compared with the standard of care 7+3 in the proposed population of patients with newly diagnosed acute myeloid leukemia (AML) with myelodysplasia-related changes and therapy-related AML. This is remarkable given the very poor prognosis of these patients and their unmet medical need. Secondary endpoints support the primary outcome, in particular an increased rate of hematopoietic stem cell transplantation, which is potentially the only curative treatment in AML.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cytarabine; Daunorubicin; Humans; Ireland; Leukemia, Myeloid, Acute; Liposomes
PubMed: 32282100
DOI: 10.1634/theoncologist.2019-0785