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This study aimed to explore the role and molecular mechanism of miR-133 in multidrug resistance in acute myeloid leukemia (AML) and provide a new theoretical basis for the treatment and prognosis of AML patients. We performed experiments at the cellular level. RT‒qPCR and Western blotting were used to detect gene and protein expression; cell viability was measured with CCK-8 assays; apoptosis was detected via flow cytometry; and a dual-luciferase reporter gene assay was used to verify the binding between miR-133 and CXCL12. In this study, we found that miR-133 was upregulated in HL-60/ADR multidrug-resistant cells. Functionally, the inhibition of miR-133 alleviated the resistance of HL-60/ADR cells to daunorubicin (DNR). After inhibiting miR-133 in HL-60/ADR cells treated with DNR, the expression of the intracellular drug resistance-related proteins MRP562 and P-gp was inhibited, cell proliferation decreased, and apoptosis increased. Mechanistically, the NF-κB signaling pathway regulates the expression of miR-133 in HL-60/ADR cells, and the targeting of CXCL12 by miR-133 enhances the resistance of HL-60/ADR cells to DNR. In conclusion, the NF-κB signaling pathway regulates the expression of miR-133, and inhibiting miR-133 expression can target CXCL12 to increase the sensitivity of HL-60/ADR cells to DNR. [ABSTRACT FROM AUTHOR]

Introduction: As a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines. Methods: In the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC. Results: Ultimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo , SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis. Discussion: In conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner. [ABSTRACT FROM AUTHOR]

Background Acute leukemia is a heterogeneous group of malignancies characterized by the rapid proliferation of immature blood cells. This study aims to compare the efficacy and safety of two different regimens of combination chemotherapy in patients diagnosed with acute leukemia. Materials and Methods A total of 120 patients with acute leukemia were randomly assigned to two treatment groups: Regimen A (cytarabine and daunorubicin) and Regimen B (cytarabine, daunorubicin, and etoposide). Patients were evaluated based on complete remission rates, overall survival, and adverse effects over a 12-month period. Results The results indicated that Regimen A achieved a complete remission rate of 70% (42 out of 60 patients), while Regimen B showed a higher rate of 80% (48 out of 60 patients). The median overall survival was 14 months for Regimen A and 18 months for Regimen B. Adverse effects were comparable, with Grade 3 or higher toxicities observed in 30% of patients in Regimen A and 25% in Regimen B. Conclusion Both regimens demonstrated significant efficacy in treating acute leukemia, with Regimen B showing superior remission rates and overall survival. Further studies are needed to confirm these findings and optimize treatment protocols. [ABSTRACT FROM AUTHOR]

In the current work, a novel and simple electrochemical sensing platform was built utilizing a graphene oxide (GO)/metal–organic framework-235 (MOF-235) nanocomposite, which was successfully synthesized and used as an excellent modifier to determine the simultaneous presence of two key anticancer medications, daunorubicin (DNR), and dacarbazine (DTIC). Fourier transform infrared spectroscopy, energy-dispersive X-ray spectroscopy, field-emission scanning electron microscopy, and scanning electron microscopy (SEM) are used to characterize the GO/MOF-235 nanocomposite. The electrocatalytic properties of the modified sensor based on MOF and GO in phosphate buffer solution (PBS) (0.1 M—pH 7.0) toward DNR redox reaction were thoroughly investigated using electrochemical methodologies including cyclic voltammetry, differential pulse voltammetry, and chronoamperometry. This GO/MOF-235-modified CPE demonstrated a wide linear response of 0.005–400.0 μM under optimized conditions. It was determined that 0.002 μM was the detection limit. This sensor displayed two distinct oxidation peaks at 390 mV for DNR and at 750 mV for dacarbazine (DTIC) (peak potential separation = 360 mV), allowing for the simultaneous detection of the two anticancer medications. Determination of these anticancer medicines in samples (DNR injection and DTIC injection) was effectively accomplished in the final step using the GO/MOF-235/CPE sensor. [ABSTRACT FROM AUTHOR]

Background & objectives: The human blood parasite Leishmania donovani causes visceral leishmaniasis or grayish discoloration of the skin (black fever/kala-azar). Antitumor drugs such as daunorubicin and etoposide can help to treat such diseases. The computational approach is used to find a better interaction of drugs with the active site of the protein and help to design new drugs. Methods: In this study, we have optimized two antitumor drugs, daunorubicin and etoposide. We studied frontier molecular orbitals, electrostatic potential (MEP) maps, and the natural bond order analysis of these anticancer drugs, followed by molecular docking with Leishmania donovani protein. Results: The three-dimensional structure of MapK from Leishmania donovani is LDBPK-331470. Our computational calculations reveal that daunorubicin and etoposide drugs can have an affinity with MapK from Leishmania donovani. Interpretation & conclusion: Our study predicted that both daunorubicin and etoposide could have a similar affinity with the protein (UvrD) Leishmania donovani.

Measuring the concentration of anticancer drugs in pharmacological and biological samples is a very useful solution to investigate the effectiveness of these drugs in the chemotherapy process. A Pt,Pd-doped, NiO-decorated SWCNTs (Pt,Pd-NiO/SWCNTs) nanocomposite was synthesized using a one-pot procedure and combining chemical precipitation and ultrasonic sonochemical methods and subsequently characterized by TEM and EDS analysis methods. The analyses results showed the high purity and good distribution of elements and the ∼10-nm diameter of the Pt,Pd-NiO nanoparticle decorated on the surface of the SWCNTs with a diameter of about 20-30 nm. Using a combination of Pt,Pd-NiO/SWCNTs and 1-butyl-2,3-dimethylimidazolium tetrafluoroborate (1B23DTFB) in a carbon paste (CP) matrix, Pt,Pd-NiO/SWCNTs/1B23DTFB/CP was fabricated as a highly sensitive analytical tool for the electrochemical determination of daunorubicin in the concentration range of 0.008-350μM with a detection limit of 3.0 nM. Compared to unmodified CP electrodes, the electro-oxidation process of daunorubicin has undergone significant improvements in current (about 9.8 times increasing in current) and potential (about 110 mV) decreasing in potential). It is noteworthy that the designed sensor can well measure daunorubicin in the presence of tamoxifen (two breast anticancer drugs with a 1E = 315mV. According to the real sample analysis data, the Pt,Pd-NiO/SWCNTs/1B23DTFB/CP has proved to be a promising methodology for the analysis and measuring of daunorubicin and tamoxifen in real (e.g., pharmaceutical) samples. [ABSTRACT FROM AUTHOR]

A new system for delivery of anthracycline antibiotics based on chitosan-polyaminoxyls (CPA) was studied in a model of non-tumor (human embryonic mesenchymal stem cells) and tumor cells (human hepatocellular carcinoma) in vitro. The presence of CPA micelles considerably suppresses daunorubicin-induced ROS generation in normal cells without affecting this process in tumor cells. CPA micelles do not reduce the cytotoxic effect of daunorubicin and do not prevent its accumulation in cells. The use of CPA significantly increases accumulation of Nrf2 transcription factor in the nuclei of both normal and tumor cells in comparison with free daunorubicin. Increased nuclear translocation of Nrf2 leads to a significant increase in the expression of its target gene TXN1, but not the NQO1, GPX1, and HMOX1 genes, the increased expression of which can lead to the development of resistance to anthracycline antibiotics. Redox-active CPA micelles have great potential for the development of nanoparticles for the transport of anthracycline antibiotics in experimental tumor chemotherapy, and also as promising activators of Nrf2 transcription factor. [ABSTRACT FROM AUTHOR]

IntroductionAs a malignant hematological disease, the incidence of acute myeloid leukemia (AML) has exhibited an upward trend in recent years. Nevertheless, certain limitations persist in the treatment of AML. Sperm-associated antigen 6 (SPAG6) has been implicated in the onset and progression of various human cancers, with its expression levels significantly elevated in AML. Consequently, we undertook a series of experiments to investigate the role and underlying mechanisms of SPAG6 in AML cell lines.MethodsIn the in vitro experiments of this study, DEPs and GO and KEGG enrichment analysis subsequent to SPAG6 down-regulation were detected by TMT. CCK8 was employed to determine cell viability. The levels of apoptosis and ROS were measured by flow cytometry. In the in vivo experiments, a xenografted tumor model was constructed, and the expression of SPAG6 and GSTP1 in tumor tissues was detected by IHC.ResultsUltimately, our findings indicated that over-expression of SPAG6 promoted cell growth and decreased reactive oxygen species (ROS) and malondialdehyde levels. Furthermore, SPAG6 knockdown was found to diminish mitochondrial membrane potential and facilitate cell apoptosis. In vivo, SPAG6 could also promote tumor growth, suggesting that SPAG6 may serve as a pro-tumor factor. In addition, daunorubicin (DNR) may cause oxidative stress and initiate apoptosis, resulting in oxidative damage to AML cells. However, the overexpression of SPAG6 may attenuate the efficacy of DNR. This was due to SPAG6 promoted GSTP1 expression, thereby reducing ROS levels. Simultaneously, the elevation of GSTP1 and JNK complex may reduce the expression of p-JNK and inhibit the activation of JNK pathway, which might inhibit cell apoptosis.DiscussionIn conclusion, our experiments suggested that upregulated SPAG6 might mitigate the pro-apoptotic effects of DNR through ROS/JNK MAPK axis in a GSTP1-dependent manner.

Objective To explore the correlation between daunorubicin (DNR) resistance and expression of programmed death receptor ligand 1 (PD-L1) in children with acute myeloid leukemia (AML). Methods Totally 110 bone marrow samples were selected from AML patients admitted to Zhengzhou University Affiliated Children's Hospital from January 2016 to December 2022 as the study group, 50 bone marrow samples from normal bone marrow donors were used as the control group. Human AML cell lines HL60, THP-1, U-937, and Molm-13 were cultured, and the expression of PD-L1 protein was detected by Western blot. LV-PD-L1-shRNA and LV-PD-L1-WT-OE lentiviral vectors were constructed. The effect and mechanism of PD-L1 on DNR resistance in Molm-13 cells were analyzed. Results The expression level of PD-L1 protein was higher than that in control group and the expression level of PD-L1 protein in AMI cell lines was higher than that in healthy bone marrow mononuclear cells (BMMC) (P＜0.05). PD-L1 expression was related to white blood cell count, bone marrow primitive cell ratio, prognostic risk stratification and disease remission after two standard chemotherapy regimens in AML patients (P＜0.05). The overall survival rate of the PD-L1 high expression group was lower than that of the PD-L1 low expression group (P＜0.05). Compared with the LV-PD-L1-WT-OE group, the LV-PD-L1-shRNA group showed a decrease in PD-L1 mRNA expression, cell proliferation activity but an increased apoptosis rate(P＜0.05). LV-PD-L1-shRNA enhanced sensitivity of Molm-13 cells to DNR. TCGA database analysis showed that glucose 6-phosphate dehydrogenase (G6PD) was a potential target gene for PD-L1. Conclusions The high expression of PD-L1 in pediatric AML is related to chemotherapy resistance in children with AML, and DNR resistance might be caused through regulation of G6PD.

Objective To explore the correlation between daunorubicin (DNR) resistance and expression of programmed death receptor ligand 1 (PD-L1) in children with acute myeloid leukemia (AML). Methods Totally 110 bone marrow samples were selected from AML patients admitted to Zhengzhou University Affiliated Children's Hospital from January 2016 to December 2022 as the study group, 50 bone marrow samples from normal bone marrow donors were used as the control group. Human AML cell lines HL60, THP-1, U-937, and Molm-13 were cultured, and the expression of PD-L1 protein was detected by Western blot. LV-PD-L1-shRNA and LV-PD-L1-WT-OE lentiviral vectors were constructed. The effect and mechanism of PD-L1 on DNR resistance in Molm-13 cells were analyzed. Results The expression level of PD-L1 protein was higher than that in control group and the expression level of PD-L1 protein in AMI cell lines was higher than that in healthy bone marrow mononuclear cells (BMMC) (P＜0.05). PD-L1 expression was related to white blood cell count, bone marrow primitive cell ratio, prognostic risk stratification and disease remission after two standard chemotherapy regimens in AML patients (P＜0.05). The overall survival rate of the PD-L1 high expression group was lower than that of the PD-L1 low expression group (P＜0.05). Compared with the LV-PD-L1-WT-OE group, the LV-PD-L1-shRNA group showed a decrease in PD-L1 mRNA expression, cell proliferation activity but an increased apoptosis rate(P＜0.05). LV-PD-L1-shRNA enhanced sensitivity of Molm-13 cells to DNR. TCGA database analysis showed that glucose 6-phosphate dehydrogenase (G6PD) was a potential target gene for PD-L1. Conclusions The high expression of PD-L1 in pediatric AML is related to chemotherapy resistance in children with AML, and DNR resistance might be caused through regulation of G6PD. [ABSTRACT FROM AUTHOR]

Objectives: NS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML. Methodology: This open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60–75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351. Results: In the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7–74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated. Outcomes: NS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML. [ABSTRACT FROM AUTHOR]

Acute myeloid leukaemia (AML) is characterized by uncontrolled proliferation of myeloid progenitor cells and impaired maturation, leading to immature cell accumulation in the bone marrow and bloodstream, resulting in hematopoietic dysfunction. Chemoresistance, hyperactivity of survival pathways, and miRNA alteration are major factors contributing to treatment failure and poor outcomes in AML patients. This study aimed to investigate the impact of the pharmacological p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on the chemoresistance potential of AML stem cell line KG1a to the therapeutic drug daunorubicin (DNR). KG1a and chemosensitive leukemic HL60 cells were treated with increasing concentrations of DNR. Cell Titer-Glo®, flow cytometry, phosphokinase and protein arrays, Western blot technology, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were employed for assessment of cell viability, half-maximal inhibitory concentration (IC50) determination, apoptotic status detection, cell cycle analysis, apoptosis-related protein and gene expression monitoring. Confocal microscopy was used to visualize caspase and mitochondrial permeability transition pore (mPTP) activities. Exposed at various incubation times, higher DNR IC50 values were determined for KG1a cells than for HL60 cells, confirming KG1a cell chemoresistance potential. Exposed to DNR, late apoptosis induction in KG1a cells was enhanced after SB203580 pretreatment, defined as the combination treatment. This enhancement was confirmed by increased cleavage of poly(ADP-ribose) polymerase, caspase-9, caspase-3, and augmented caspase-3/-7 and mPTP activities in KG1a cells upon combination treatment, compared to DNR. Using phosphokinase and apoptosis protein arrays, the combination treatment decreased survival Akt phosphorylation and anti-apoptotic Bcl-2 expression levels in KG1a cells while increasing the expression levels of the tumor suppressor p53 and cyclin-dependent kinase inhibitor p21, compared to DNR. Cell cycle analysis revealed KG1a cell growth arrest in G2/M-phase caused by DNR, while combined treatment led to cell growth arrest in S-phase, mainly associated with cyclin B1 expression levels. Remarkably, the enhanced KG1a cell sensitivity to DNR after SB203580 pretreatment was associated with an increased upregulation of miR-328-3p and slight downregulation of miR-26b-5p, compared to DNR effect. Altogether, these findings could contribute to the development of a new therapeutic strategy by targeting the p38 MAPK pathway to improve treatment outcomes in patients with refractory or relapsed AML.

Abstract Background Recent achievements in cancer therapy are the use of alternating electrical fields at intermediate frequencies (100–300 kHz) and low intensities (1–3 V/cm), which specifically target cell proliferation while affecting different cellular activities depending on the frequency used. Methods In this article, we examine the effect of electric fields on spherical suspended cells and propose the combination of Daunorubicin, a chemotherapy agent widely used in the treatment of acute myeloid leukemia, with electric field exposure. U937 cells were subjected to an electric field with a frequency of 200 kHz and an intensity of 0.75 V/cm, or to a combination of Daunorubicin and electric field exposure, resulting in a significant reduction in cell proliferation. Furthermore, the application of an electric field to U937 cells increased Daunorubicin uptake. Results Apoptosis and DNA damage were induced by the electric field or in conjunction with Daunorubicin. Notably, normal cells exposed to an electric field did not show significant damage, indicating a selective effect on dividing cancer cells (U937). Moreover, the electric field affects the U937 cell line either alone or in combination with Daunorubicin. This effect may be due to increased membrane permeability. Conclusions Our findings suggest that the use of electric fields at intermediate frequencies and low intensities, either alone or in combination with Daunorubicin, has potential as a selective anti-cancer therapy for dividing cancer cells, particularly in the treatment of acute myeloid leukemia. Further research is needed to fully understand the underlying mechanisms and to optimize the use of this therapy.

Purpose: Chemotherapy drugs used to treat lung cancer are associated with drug resistance and severe side effects. There have been rising demands for new therapeutic candidates and novel approaches, including combination therapy. Here, we aimed to investigate the combinatorial effect of a dendrosomal formulation of curcumin (DNC) and daunorubicin (DNR) on the A549 lung cancer cell line. Methods: We performed cytotoxicity, apoptosis, cell migration, colony-formation capacity, and gene expression analysis to interpret the mechanism of action for a combination of DNC and DNR on A549 cells. Results: Our results revealed that the combination of DNC and DNR could synergistically inhibit the A549 cells’ growth. This synergistic cytotoxicity was further approved by flow cytometry, migration assessment, colony-forming capacity and gene expression analysis. DNR combination with DNC resulted in increased apoptosis to necrosis ratio compared to DNR alone. In addition, the migration and colony-forming capacity were at the minimal range when DNC was combined with DNR. Combined treatment decreased the expression level of MDR-1, hTERT and Bcl-2 genes significantly. In addition, the ratio of Bax/Bcl2 gene expression significantly increased. Our analysis by free curcumin, dendrosomes and DNC also showed that dendrosomes do not have any significant cytotoxic effect on the A549 cells, suggesting that this carrier has a high potential for enhancing the curcumin’s biological effects. Conclusion: Our observations suggest that the DNC formulation of curcumin synergistically enhances the antineoplastic effect of DNR on the A549 cell line through the modulation of apoptosis/necrosis ratio, as well as Bax/Bcl2 ratio, MDR-1 and hTERT gene expression.

An environmental friendly, fast, easy and inexpensive liquid-liquid microextraction (LLME) in combination with pH-switchable deep eutectic solvent (DES) method followed by HPLC was investigated for the separation and determination of daunorubicin (DNR) in human plasma samples. For this purpose, first, 9 DESs were prepared based on previous studies and their switchability in aqueous solution was evaluated by changing the pH. Non-switchable DESs were discarded and switchable DESs were used to extract DNR. The parameters affecting the extraction efficiency were optimized (DES type, volume of DES, concentration of KOH, volume of HCl, salt addition and extraction time). After optimizing the conditions and drawing the calibration curve, figures of merit were calculated. Relative standard deviations (%RSDs) based on 7 replicate with 50 μg L−1 of DNR in plasma were 2.7 for intra-day and 4.8 % for inter-day. A wide linear range from 0.15 to 200 μg L−1 was obtained. The detection limit of the method based on signal-to-noise 3 and the quantification limit of the method based on signal-to-noise 10 were 0.05 and 0.15, respectively. After spiking plasma samples with different concentrations of DNR, relative recoveries were obtained in the range of 91.0–107.8 %.

Background and purpose: Daunorubicin is an effective drug in chemotherapy, but its clinical use is limited due to serious side effects. Royal jelly as a natural compound obtained from bees can be helpful in preventing the damage caused by daunorubicin. The present study aimed to evaluate the effects of royal jelly on the number of apoptotic cells and the expression of genes involved in apoptosis in mice treated with daunorubicin. Materials and methods: In this experimental study, 77 Balb/c mice were randomly divided into seven groups (n= 11 per group): sham, control, royal jelly (50 and 100 mg/kg), daunorubicin (2 mg/kg), and royal jelly (50 and 100 mg/kg) + daunorubicin. The mice received saline (0.09%), IP daunorubicin, and royal jelly orally for eight weeks. To estimate the number of apoptotic cells and the expression of genes related to apoptosis in testis, we used ELISA test and Real-time PCR assay, respectively. Data analysis was done applying One-way Analysis of Variance and Tukey's test in SPSS. Results: Daunorubicin caused significant increase in the number of apoptotic cells, and expression levels of p53, Bax, caspase 3, caspase 8, and caspase 9 (P

Simple Summary: Despite promising results of clinical trials, the use of immune checkpoint inhibitors (ICI) in acute myeloid leukaemia (AML) remains limited. To date, the United States Food and Drug Administration (FDA) has approved two PD-1 inhibitors, namely nivolumab and pembrolizumab, for treating relapsed/refractory classical Hodgkin lymphoma, and pembrolizumab in primary mediastinal large B-cell lymphoma. In AML, the potential of ICM inhibitors, namely PD-1, PD-L1, and CTLA-4 blockers, was confirmed in clinical trials in relapsed or refractory disease or in high-risk patients. However, the response rate varied widely, possibly due to the heterogeneity of the ICM expression level within different AML cases. Flow cytometric analysis was used for analysing PD-1, PD-L1, CTLA-4, and B7-H3 in untreated AML patients stratified on the basis of clinical outcome and cytogenetic molecular risk. Here, we demonstrated association of selected ICI in AML patients with their response to therapy and overall survival. The development of novel drugs with different mechanisms of action has dramatically changed the treatment landscape of AML patients in recent years. Considering a significant dysregulation of the immune system, inhibitors of immune checkpoint (ICI) proteins provide a substantial therapeutic option for those subjects. However, use of ICI in haematological malignancies remains very limited, in contrast to their wide use in solid tumours. Here, we analysed expression patterns of the most promising selected checkpoint-based therapeutic targets in AML patients. Peripheral blood of 72 untreated AML patients was used for flow cytometric analysis. Expression of PD-1, PD-L1, CTLA-4, and B7-H3 was assessed within CD4+ (Th) lymphocytes and CD33+ blast cells. Patients were stratified based on therapy outcome and cytogenetic molecular risk. AML non-responders (NR) showed a higher frequency of PD-1 in Th cells compared to those with complete remission (CR). Reduced blast cell level of CTLA-4 was another factor differentiating CR from NR subjects. Elevated levels of PD-1 were associated with a trend for poorer patients' survival. Additionally, prognosis for AML patients was worse in case of a higher frequency of B7-H3 in Th lymphocytes. In summary, we showed the significance of selected ICI as outcome predictors in AML management. Further, multicentre studies are required for validation of those data. [ABSTRACT FROM AUTHOR]

Background: Recent achievements in cancer therapy are the use of alternating electrical fields at intermediate frequencies (100–300 kHz) and low intensities (1–3 V/cm), which specifically target cell proliferation while affecting different cellular activities depending on the frequency used. Methods: In this article, we examine the effect of electric fields on spherical suspended cells and propose the combination of Daunorubicin, a chemotherapy agent widely used in the treatment of acute myeloid leukemia, with electric field exposure. U937 cells were subjected to an electric field with a frequency of 200 kHz and an intensity of 0.75 V/cm, or to a combination of Daunorubicin and electric field exposure, resulting in a significant reduction in cell proliferation. Furthermore, the application of an electric field to U937 cells increased Daunorubicin uptake. Results: Apoptosis and DNA damage were induced by the electric field or in conjunction with Daunorubicin. Notably, normal cells exposed to an electric field did not show significant damage, indicating a selective effect on dividing cancer cells (U937). Moreover, the electric field affects the U937 cell line either alone or in combination with Daunorubicin. This effect may be due to increased membrane permeability. Conclusions: Our findings suggest that the use of electric fields at intermediate frequencies and low intensities, either alone or in combination with Daunorubicin, has potential as a selective anti-cancer therapy for dividing cancer cells, particularly in the treatment of acute myeloid leukemia. Further research is needed to fully understand the underlying mechanisms and to optimize the use of this therapy. [ABSTRACT FROM AUTHOR]

Background: Obesity (body mass index [BMI] ≥30 kg/m2) is an important epidemiological risk factor for developing acute myeloid leukemia (AML). Therefore, the authors studied the association of obesity with clinical and genetic phenotype and its impact on outcome in adults with AML. Methods: The authors analyzed BMI in 1088 adults who were receiving intensive remission induction and consolidation therapy in two prospective, randomized therapeutic clinical trials of the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network: E1900 (ClinicalTrials.gov identifier NCT00049517; patients younger than 60 years) and E3999 (ClinicalTrials.gov identifier NCT00046930; patients aged 60 years or older). Results: Obesity was prevalent at diagnosis (33%) and, compared with nonobesity, was associated with intermediate‐risk cytogenetics group (p =.008), poorer performance status (p =.01), and a trend toward older age (p =.06). Obesity was not associated with somatic mutations among a selected 18‐gene panel that was tested in a subset of younger patients. Obesity was not associated with clinical outcome (including complete remission, early death, or overall survival), and the authors did not identify any patient subgroup that had inferior outcomes based on BMI. Obese patients were significantly more likely to receive <90% of the intended daunorubicin dose despite protocol specification, particularly in the E1900 high‐dose (90 mg/m2) daunorubicin arm (p =.002); however, this did not correlate with inferior overall survival on multivariate analysis (hazard ratio, 1.39; 95% confidence interval, 0.90–2.13; p =.14). Conclusions: Obesity is associated with unique clinical and disease‐related phenotypic features in AML and may influence physician treatment decisions regarding daunorubicin dosing. However, the current study demonstrates that obesity is not a factor in survival, and strict adherence to body surface area‐based dosing is not necessary because dose adjustments do not affect outcomes. Obesity is prevalent in adults with acute myeloid leukemia, and these patients are more likely to have intermediate‐risk cytogenetics and worse performance status; however, obesity does not affect clinical outcomes, including complete remission, early death, or overall survival. Dose modifications of daunorubicin (dose reductions and dose capping) in obese patients does not affect clinical outcomes; therefore, strict adherence to the full dose based on body surface area is not required for intensive therapy in adults with acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Chemotherapy drugs used to treat lung cancer are associated with drug resistance and severe side effects. There have been rising demands for new therapeutic candidates and novel approaches, including combination therapy. Here, we aimed to investigate the combinatorial effect of a dendrosomal formulation of curcumin (DNC) and daunorubicin (DNR) on the A549 lung cancer cell line. Methods: We performed cytotoxicity, apoptosis, cell migration, colony-formation capacity, and gene expression analysis to interpret the mechanism of action for a combination of DNC and DNR on A549 cells. Results: Our results revealed that the combination of DNC and DNR could synergistically inhibit the A549 cells' growth. This synergistic cytotoxicity was further approved by flow cytometry, migration assessment, colony-forming capacity and gene expression analysis. DNR combination with DNC resulted in increased apoptosis to necrosis ratio compared to DNR alone. In addition, the migration and colony-forming capacity were at the minimal range when DNC was combined with DNR. Combined treatment decreased the expression level of MDR-1, hTERT and Bcl-2 genes significantly. In addition, the ratio of Bax/Bcl2 gene expression significantly increased. Our analysis by free curcumin, dendrosomes and DNC also showed that dendrosomes do not have any significant cytotoxic effect on the A549 cells, suggesting that this carrier has a high potential for enhancing the curcumin's biological effects. Conclusion: Our observations suggest that the DNC formulation of curcumin synergistically enhances the antineoplastic effect of DNR on the A549 cell line through the modulation of apoptosis/necrosis ratio, as well as Bax/Bcl2 ratio, MDR-1 and hTERT gene expression. [ABSTRACT FROM AUTHOR]

Yuanyuan Zhu, Wei Zhang, Jing Chen Department of Pharmacy, Qingdao Hospital of Traditional Chinese Medicine, Qingdao Hiser Hospital Affiliated with Qingdao University, Qingdao, Shandong Province, People’s Republic of ChinaCorrespondence: Jing Chen, Department of Pharmacy, Qingdao Hospital of Traditional Chinese Medicine, Qingdao Hiser Hospital Affiliated with Qingdao University, 4 Renmin Road, Qingdao, Shandong Province, 266000, People’s Republic of China, Email chenjingqdu@outlook.comObjective: This study aimed to develop a binary nanodrug-delivery system decorated with aptamers (APs) and transferrin (Tf) and loaded with daunorubicin (Drn) and luteolin (Lut) for the treatment of leukemia.Methods: Oligonucleotide AP- and Tf-contaiing ligands were designed and synthesized separately. AP-decorated Drn-loaded nanoparticles (AP-Drn NPs) and Tf-Lut NPs were prepared by self-assembly. An AP- and Tf-codecorated Drn- and Lut-coloaded nanodrug-delivery system (AP/Tf-Drn/Lut NPs) was prepared by self-assembly of AP-Drn NPs and Tf-Lut NPs. In vitro and in vivo efficiency of the system was evaluated on leukemia cell line and cell-bearing mouse model in comparison with single ligand–decorated, single drug–loaded and free-drug formulations.Results: AP/Tf-Drn/Lut NPs were spherical and nanosized (187.3± 5.3 nm) and loaded with about 85% of drugs. In vitro cytotoxicity of AP/Tf-Drn/Lut NPs was remarkably higher than single ligand–decorated ones. Double drug–loaded AP/Tf-Drn/Lut NPs exhibited higher tumor-cell inhibition than single drug–loaded ones, which showed a synergic effect of the two drugs. AP/Tf-Drn/Lut NPs achieved the most efficient antileukemic activity and absence of toxicity in vivo.Conclusion: The present study showed that AP/Tf-Drn/Lut NPs are a promising drug-delivery system for targeted treatment of leukemia, due to the synergic effect of the two drugs in this system. The limitations of this system include stability during large-scale production and application from bench to bedside.Keywords: acute myeloid leukemia, daunorubicin, luteolin, aptamer, transferrin, nanodrug-delivery system

Abstract Background DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. Method AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells’ sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in AML cells carried DNMT3A R882H mutation. Results AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells’ sensitivity to daunorubicin significantly. Conclusion Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. Video abstract

Background and purpose: Daunorubicin is an effective drug in chemotherapy, but its clinical use is limited due to serious side effects. Royal jelly as a natural compound obtained from bees can be helpful in preventing the damage caused by daunorubicin. The present study aimed to evaluate the effects of royal jelly on the number of apoptotic cells and the expression of genes involved in apoptosis in mice treated with daunorubicin. Materials and methods: In this experimental study, 77 Balb/c mice were randomly divided into seven groups (n= 11 per group): sham, control, royal jelly (50 and 100 mg/kg), daunorubicin (2 mg/kg), and royal jelly (50 and 100 mg/kg) + daunorubicin. The mice received saline (0.09%), IP daunorubicin, and royal jelly orally for eight weeks. To estimate the number of apoptotic cells and the expression of genes related to apoptosis in testis, we used ELISA test and Real-time PCR assay, respectively. Data analysis was done applying One-way Analysis of Variance and Tukey's test in SPSS. Results: Daunorubicin caused significant increase in the number of apoptotic cells, and expression levels of p53, Bax, caspase 3, caspase 8, and caspase 9 (P<0.01) and a significant decrease in the bcl-2 gene expression (P<0.01). In treatment groups, these changes were moderated by royal jelly. Conclusion: Royal jelly administration, by reducing the number of apoptotic cells and affecting the expression of genes involved in apoptosis, improves the damage caused by daunorubicin on the testicular tissue of mice. [ABSTRACT FROM AUTHOR]

Drugs and pharmaceuticals are an emergent class of aquatic contaminants. The existence of these pollutants in aquatic bodies is currently raising escalating concerns because of their negative impact on the ecosystem. This study investigated the efficacy of two sorbents derived from orange peels (OP) biochar (OPBC) for the removal of the antineoplastic drug daunorubicin (DNB) from pharmaceutical wastewater. The adsorbents included pristine (OPBC) and magnetite (Fe3O4)-impregnated (MAG-OPBC) biochars. Waste-derived materials offer a sustainable and cost-effective solution to wastewater bioremediation. The results showed that impregnation with Fe3O4 altered the crystallization degree and increased the surface area from 6.99 m2/g in OPBC to 60.76 m2/g in the case of MAG-OPBC. Placket–Burman Design (PBD) was employed to conduct batch adsorption experiments. The removal efficiency of MAG-OPBC (98.51%) was higher compared to OPBC (86.46%). DNB adsorption onto OPBC followed the D–R isotherm, compared to the Langmuir isotherm in the case of MAG-OPBC. The maximum adsorption capacity (qmax) was 172.43 mg/g for MAG-OPBC and 83.75 mg/g for OPBC. The adsorption kinetics for both sorbents fitted well with the pseudo-second-order (PSO) model. The results indicate that MAG-OPBC is a promising adsorbent for treating pharmaceutical wastewater. [ABSTRACT FROM AUTHOR]

Doxorubicin is one of the most widely used antitumor drugs and is currently produced via the chemical conversion method, which suffers from high production costs, complex product separation processes, and serious environmental pollution. Biocatalysis is considered a more efficient and environment-friendly method for drug production. The cytochrome daunorubicin C-14 hydroxylase (DoxA) is the essential enzyme catalyzing the conversion of daunorubicin to doxorubicin. Herein, the DoxA from Streptomyces peucetius subsp. caesius ATCC 27952 was expressed in Escherichia coli, and the rational design strategy was further applied to improve the enzyme activity. Eight amino acid residues were identified as the key sites via molecular docking. Using a constructed screening library, we obtained the mutant DoxA(P88Y) with a more rational protein conformation, and a 56% increase in bioconversion efficiency was achieved by the mutant compared to the wild-type DoxA. Molecular dynamics simulation was applied to understand the relationship between the enzyme's structural property and its substrate-binding efficiency. It was demonstrated that the mutant DoxA(P88Y) formed a new hydrophobic interaction with the substrate daunorubicin, which might have enhanced the binding stability and thus improved the catalytic activity. Our work lays a foundation for further exploration of DoxA and facilitates the industrial process of bio-production of doxorubicin. [ABSTRACT FROM AUTHOR]

Simple Summary: The interactions between Acute Myeloid Leukaemia (AML) cells and the surrounding bone marrow (BM) tissue contribute to blocking the efficacy of current drug treatments and to the relapse of patients. Relapsing AML tumours are refractory to current therapies and remain untreatable. Developing new therapies for AML requires the development of new drug-screening methods using in vitro models that closely mimic the interactions of AML cells with cytoprotective BM cells. We have developed a new fluorescence-based in vitro model and an analytical method that takes into consideration the reciprocal interactions between AML cells and the protective BM stroma during drug treatments. Using this new method and combining it with bioinformatics, we have identified new combinations of drugs that may overcome resistance to drug treatments and lead to improved therapies for AML. The interactions between Acute Myeloid Leukaemia (AML) leukemic stem cells and the bone marrow (BM) microenvironment play a critical role during AML progression and resistance to drug treatments. Therefore, the identification of novel therapies requires drug-screening methods using in vitro co-culture models that closely recreate the cytoprotective BM setting. We have developed a new fluorescence-based in vitro co-culture system scalable to high throughput for measuring the concomitant effect of drugs on AML cells and the cytoprotective BM microenvironment. eGFP-expressing AML cells are co-cultured in direct contact with mCherry-expressing BM stromal cells for the accurate assessment of proliferation, viability, and signaling in both cell types. This model identified several efficacious compounds that overcome BM stroma-mediated drug resistance against daunorubicin, including the chromosome region maintenance 1 (CRM1/XPO1) inhibitor KPT-330. In silico analysis of genes co-expressed with CRM1, combined with in vitro experiments using our new methodology, also indicates that the combination of KPT-330 with the AURKA pharmacological inhibitor alisertib circumvents the cytoprotection of AML cells mediated by the BM stroma. This new experimental model and analysis provide a more precise screening method for developing improved therapeutics targeting AML cells within the cytoprotective BM microenvironment. [ABSTRACT FROM AUTHOR]

Background: Although significant advances have been made in the treatment of cancer, a significant number of patients with acute lymphoblastic leukemia (ALL) show resistance to treatment. Thus, it is necessary to seek novel therapeutic agents to overcome this problem. Studies have indicated that the expression level of mouse double minute 2 (MDM2), a negative regulator of p53, is markedly elevated in patients with refractory or recurrent ALL. Thus, targeting MDM2 using a specific inhibitor, Idasanutlin, can increase the activity of p53. This study evaluated the possible synergistic effect of Idasanutlin and Daunorubicin on the induction of apoptosis in NALM-6 cells. Materials and methods: In this fundamental study, the anti-proliferative effects of Idasanutlin on NALM-6 cells, either alone or in combination with Daunorubicin, were confirmed by MTT(methyl-thiazol-tetrazolium) assay, Annexin/PI apoptosis assay, and cell cycle analysis. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were applied to elucidate the molecular mechanisms underlying the anti-leukemic activity of Idasanutlin. Results: Idasanutlin synergistically enhanced Daunorubicin-induced apoptosis and activated caspase-3, thereby activating programmed cell death in a dose-dependent manner (P<0.001). The treatment of NALM-6 cells with Idasanutlin caused cell cycle arrest in the G1 phase by an increase in the expression of p21 (P<0.001). Moreover, a significant increase was detected in the expression of pro-apoptotic genes (P<0.001), as well as a remarkable decrease in the expression of anti-apoptotic (P<0.01) and multidrug resistance1 (MDR1) genes (P<0.01). Conclusions: It seems that Idasanutlin can cooperatively promote daunorubicin-induced apoptosis in NALM-6 cells. These findings open up a new horizon in the application of Idasanutlin in combination with Daunorubicin to overcome drug resistance in patients with ALL. [ABSTRACT FROM AUTHOR]

The aim of this study was to develop casein-based nanoscale carriers as a potential delivery system for daunorubicin, as a pH-responsive targeting tool for acute lymphocytic leukemia. A coacervation technique followed by nano spray-drying was used for the preparation of drug-loaded casein nanoparticles. Four batches of drug-loaded formulations were developed at varied drug–polymer ratios using a simple coacervation technique followed by spray-drying. They were further characterized using scanning electron microscopy, dynamic light scattering, FTIR spectroscopy, XRD diffractometry, and differential scanning calorimetry. Drug release was investigated in different media (pH 5 and 7.4). The cytotoxicity of the daunorubicin-loaded nanoparticles was compared to that of the pure drug. The influence of the polymer-to-drug ratio on the nanoparticles' properties such as their particle size, surface morphology, production yield, drug loading, entrapment efficiency, and drug release behavior was studied. Furthermore, the cytotoxicity of the drug-loaded nanoparticles was investigated confirming their potential as carriers for daunorubicin delivery. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

• Size-based separation of VYXEOS® liposomes. • Cytarabine to daunorubicin ration increase with size increase of liposomes. • Lipid excipient composition was regardless size of liposomes. VYXEOS® is the first FDA-approved dual-API liposomal formulation containing two different chemotherapeutics, daunorubicin and cytarabine at a 1:5 molar ratio. Analysis of bulk formulation does not provide insight to size-based distribution of APIs and excipients, therefore asymmetrical flow field-flow fractionation (AF4) was utilized for the size-based separation of VYXEOS® liposomes and collected size fractions were further analyzed for the concentrations of APIs, lipid excipients, and copper. Analysis results revealed a significant variation in API distribution across the size fractions, with the larger liposomes encapsulating a higher ratio of cytarabine to daunorubicin compared to the smaller liposomes, while lipid excipient composition was held constant across the size range. We attribute the size-based variation of API ratios to structural change during API loading and sequence of API loading. Cytarabine is first passively loaded into liposomes containing copper gluconate, and then daunorubicin is actively loaded using copper gradient where the daunorubicin is retained in the liposomes as a copper complex. This method can be extended to characterize various single and dual-API liposomal nanocarriers during drug product development and/or post market quality control. [ABSTRACT FROM AUTHOR]

Several types of chemotherapeutic agents are used in cancer treatment. Among these agents, daunorubicin hydrochloride which is a cell-cycle non-specific antitumor agent is commonly used for treating various types of cancers. This work aims to design daunorubicin loaded polymeric fibre meshes with melt electrospinning using poly (ε-caprolactone) (PCL) polymer for potential localized antitumor application. The prepared meshes had smooth surface with uniform distribution of daunorubicin as indicated by fluorescent microscope. The meshes thickness increased by increasing the daunorubicin concentration loaded into the PCL fibres. The process of melt electrospinning did not result in any chemical interactions between PCL and daunorubicin neither changed the crystalline structure of these components. Concentration dependent slow-release profile of daunorubicin from the melt electrospun fibres was achieved. Cytotoxicity of the released daunorubicin was assessed on melanoma and ovarian cancer cells and revealed that the cytotoxicity was increased by increasing the time of meshes incubation due to the slow-release profile of daunorubicin. These results prove that PCL-based fibre meshes loaded with daunorubicin are a suitable therapeutic option for local application of antitumour agents. This can enhance the therapeutic outcomes and reduce the unwanted toxicities of these anticancer molecules. [Display omitted] [ABSTRACT FROM AUTHOR]

Background and Aim: Daunorubicin is an effective antibiotic for the chemotherapy of various cancers. To prevent damage to healthy cells during chemotherapy, it is recommended to change this treatment or protect healthy cells from chemotherapeutic agents by protective compounds. The present study aimed to check the protective effect of royal jelly on male reproductive system against the side effects induced by daunorubicin injection in mice. Materials and Methods: In this study, 77 adult BALB/c mice were randomly divided into seven groups including sham, control, royal jelly 1, royal jelly 2, daunorubicin, royal jelly 1+daunorubicin, and royal jelly 2+daunorubicin. Mice received saline (0.09%), and daunorubicin (2 mg/kg) intraperitoneally, and royal jelly (50 and 100 mg/kg) orally for 8weeks. The sperm parameters, testis weight, and oxidative stress parameters were evaluated. Using SPSS software (version 16), data were analyzed by one-way analysis of variance and Tukey test. P

Kwanza Price,1 Zhun Cao,2 Craig Lipkin,2 Deb Profant,1 Scott Robinson2 1Jazz Pharmaceuticals, Palo Alto, CA, USA; 2Premier Inc., Charlotte, NC, USACorrespondence: Deb ProfantJazz Pharmaceuticals, 3170 Porter Dr., Palo Alto, CA, 94304, USATel/Fax +1 971 409 6166Email deb.profant@jazzpharma.comPurpose: CPX-351 is dual-drug liposomal encapsulation of daunorubicin and cytarabine at a fixed synergistic 1:5 molar ratio. This study determined current real-world use of CPX-351 versus conventional 7+3 (cytarabine+daunorubicin) therapy and evaluated hospital length of stay (LOS) and supportive care utilization in t-AML and AML-MRC.Patients and Methods: This retrospective, observational study utilized the Premier Healthcare Database and included patients who were aged ≥ 18 years with t-AML or AML-MRC and treated with CPX-351 or 7+3 between August 1, 2017 and February 28, 2019. All patients treated with 7+3 were required to be eligible for CPX-351 based on its FDA-approved indication. Outcome variables were annualized and adjusted for patient, hospital, and clinical confounding factors. The primary outcome was inpatient LOS. Secondary outcomes included use of blood products and use of anti-infectives.Results: The study included 195 qualifying patients treated with CPX-351 and 160 patients treated with 7+3 who were eligible for CPX-351. Approximately one-third of the patients treated with CPX-351 were administered therapy in a hospital-based outpatient setting, and all patients treated with 7+3 received it in the inpatient setting. The regression-adjusted annualized inpatient LOS was shorter with CPX-351 than 7+3 (mean of 183.7 vs 197.1 days, p< 0.001). The difference in mean-adjusted LOS was most pronounced for t-AML, with a mean-adjusted LOS of 168.9 versus 192.5 days for CPX-351 versus 7+3, respectively (nominal p< 0.001). Supportive care utilization, including the number of administrations of red blood cells, the number of administrations of platelets, and the number of days on anti-infectives, was similar between treatment groups.Conclusion: CPX-351 was associated with a shorter inpatient LOS than 7+3. Supportive care use, including blood products and anti-infectives, was similar for CPX-351 and 7+3. These findings suggest CPX-351 conveys resource advantages over 7+3 in patients with newly diagnosed t-AML and AML-MRC.Keywords: acute myeloid leukemia, chemotherapy, cytarabine, daunorubicin, anthracycline, healthcare resource utilization

Keywords: Secondary acute myeloid leukemia; overall survival; daunorubicin; cytarabine; Haploidentical allogeneic stem cells transplantation EN Secondary acute myeloid leukemia overall survival daunorubicin cytarabine Haploidentical allogeneic stem cells transplantation 1355 1357 3 08/08/23 20230701 NES 230701 Acute myeloid leukemia (AML) is a heterogeneous disease characterized by an excessive proliferation of myeloid precursors in the blood and the bone marrow. However, a few studies have pointed out a greater risk of t-MDS/AML as a late complication of PRRT/peptide receptor chemo radionuclide therapy. Concomitant radiosensitizing chemotherapy with PRRT/PRCRT still plays an important debulking role in NEN patients with high disease burden or biologically aggressive disease, thus t-AML will continue to remain an important issue, particularly in this group of patients. [Extracted from the article]

The adsorption of anticancer drug daunorubicin from aqueous solution by carbonaceous adsorbents was investigated. The adsorption performances of graphene oxide (GO), activated carbon (AC), and multiwalled carbon nanotubes (MWCNTs) were compared. The effects of solution pH, contact time, and initial daunorubicin concentration on the removal of daunorubicin were explored. Isotherm and kinetic models were applied to predict the efficiency of the adsorbents. The major functional groups of the adsorbents were identified by FTIR spectroscopy. In alkaline medium, adsorption increases with increasing pH value. With increasing initial concentration, adsorption capacity increases and removal efficiency decreases. Kinetic studies showed that the pseudo‐second‐order model describes adsorption onto GO well, whereas the intraparticle diffusion model gives the best fits for AC and MWCNTs. The adsorption isotherm fits the Langmuir model very well. [ABSTRACT FROM AUTHOR]

Transposable elements (TEs) are abundant in genomes. Their mobilization can lead to genetic variability that is useful for evolution, but can also have deleterious biological effects. Somatic mobilization (SM) has been linked to degenerative diseases, such as Alzheimer's disease and cancer. We used a Drosophila simulans strain, in which SM can be measured by counting red spots in the eyes, to investigate how chemotherapeutic agents affect expression and SM of the mariner TE. Flies were treated with Cisplatin, Dacarbazine, and Daunorubicin. After acute exposure, relative expression of mariner was quantified by RT-qPCR and oxidative stress was measured by biochemical assays. Exposure to 50 and 100 µg/mL Cisplatin increased mariner expression and ROS levels; catalase activity increased at 100 µg/mL. With chronic exposure, the number of spots also increased, indicating higher mariner SM. Dacarbazine (50 and 100 µg/mL) did not significantly alter mariner expression or mobilization or ROS levels, but decreased catalase activity (100 µg/mL). Daunorubicin (25 and 50 µM) increased mariner expression, but decreased mariner SM. ROS and catalase activity were also reduced. Our data suggest that stress factors may differentially affect the expression and SM of TEs. The increase in mariner transposase gene expression is necessary, but not sufficient for mariner SM. [ABSTRACT FROM AUTHOR]

Background: DNA methyltransferase 3A (DNMT3A) often mutate on arginine 882 (DNMT3AR882) in acute myeloid leukemia (AML). AML patients with DNMT3A R882 mutation are usually resistant to daunorubicin treatment; however, the associated mechanism is still unclear. Therefore, it is urgent to investigate daunorubicin resistance in AML patients with DNMT3A R882 mutant. Method: AML cell lines with DNMT3A-wild type (DNMT3A-WT), and DNMT3A-Arg882His (DNMT3A-R882H) mutation were constructed to investigate the role of DNMT3A R882H mutation on cell proliferation, apoptosis and cells' sensitivity to Danunorubin. Bioinformatics was used to analyze the role of nuclear factor-E2-related factor (NRF2) in AML patients with DNMT3A R882 mutation. The regulatory mechanism of DNMT3A R882H mutation on NRF2 was studied by Bisulfite Sequencing and CO-IP. NRF2 inhibitor Brusatol (Bru) was used to explore the role of NRF2 in AML cells carried DNMT3A R882H mutation. Results: AML cells with a DNMT3A R882H mutation showed high proliferative and anti-apoptotic activities. In addition, mutant cells were less sensitive to daunorubicin and had a higher NRF2 expression compared with those in WT cells. Furthermore, the NRF2/NQO1 pathway was activated in mutant cells in response to daunorubicin treatment. DNMT3A R882H mutation regulated the expression of NRF2 via influencing protein stability rather than decreasing methylation of NRF2 promoter. Also, NRF2/NQO1 pathway inhibition improved mutant cells' sensitivity to daunorubicin significantly. Conclusion: Our findings identified NRF2 as an important player in the regulation of cell apoptosis through which helps mediate chemoresistance to daunorubicin in AML cells with DNMT3A R882H mutation. Targeting NRF2 might be a novel therapeutic approach to treat AML patients with a DNMT3A R882H mutation. 9jD1n7ooVY8uHe1s9Su8KL Video abstract [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Fighting against tumors is an ongoing challenge in both medicinal and clinical applications. In recent years, chemotherapy, along with surgery, has significantly improved the situation to prolong life expectancy. Theoretically, and regardless of dosage, we now have drugs that are strong enough to eliminate most tumors. However, due to uncontrollable drug distribution in the body, it is difficult to increase treatment efficiency by simply increasing dosages. For this reason, the need for a drug delivery system that can release “bombs” at the target organ or tissue as precisely as possible has elicited the interest of researchers. In our work, we design and construct a silica-based nanocomposite to meet the above demand. The novel nanocomposite drug carrier can be guided to target tumors or tissue by a magnetic field, since it is constructed with superparamagnetic Fe3O4 as the core. The Fe3O4 core is clad in a mesoporous silica molecular sieve MCM-41 (represented as MS, in this article), since this MS has enormous ordered hexagonal caves providing sufficient space to hold the drug molecules. To modify the magnetically guided carriers so that they become both magnetically guided and light-responsive, benzophenone hydrazone is coupled into the molecular sieve tunnel. When a certain wavelength of light is imposed on the gating molecules, C=N double bonds vibrate and swing, causing the cavity that holds the drug molecules to change size and open the tunnels. Hence, the nanocomposite has the ability to release loaded drugs with light irradiation. The structure, loading abilities, and the size of the nanocomposite are inspected with a scanning electron microscope, a transmission electron microscope, thermogravimetry analysis, N2 adsorption/desorption, and dynamic light scattering The biocompatibility and in vitro drug molecule controlled release are tested with an SMMC-7721 cell line.

The present study investigates the use of UV light and the ozone process for doxorubicin, daunorubicin, epirubicin, and irinotecan degradation. The process was carried out using different pH values in hospital wastewater. The use of UV radiation reduces the concentration of anticancer drugs, but in all cases, this technology was not able enough to remove on the whole these contaminants from hospital wastewater. The best condition was achieved when using pH 9 for most of the analytes. Doxorubicin, daunorubicin, and epirubicin were degraded at 97.3%, 88.3%, and 99.0%, respectively. Irinotecan showed the lowest degradation, just 55.6%; a slightly higher degradation (63.8%) was obtained when pH 5 was used. Complete removal of doxorubicin, daunorubicin, epirubicin, and irinotecan was achieved when ozone treatment was used for all the pH studied. The results indicated that UV light and the ozone process can be used as a tertiary treatment to reduce the concentration of anticancer drugs in the effluents. Ozonation, therefore, proved to be more efficient than the photolysis process, when considering the percentual degradation of the original compounds in shorter timespans. [ABSTRACT FROM AUTHOR]

In this study, the synthesis and use of highly efficient hydrophilic silica aerogels to remove cytotoxic chemotherapy drugs, Daunorubicin (DAU) and Doxorubicin (DOX), from synthetic pharmaceutical wastewater are reported. DOX/DAU Adsorption studies revealed the high adsorption capacity of the hydrophilic sample. Optimal adsorbent dosage and solution pH for DAU/DOX adsorption was 0.15 g and pH = 10, respectively. Results of kinetic studies demonstrated that the equilibrium time for DAU/DOX adsorption was within 60 minutes, and the pseudo 2nd order model best fitted to the adsorption experimental data. The results of the intra-particle diffusion model showed that the DAU/DOX adsorption process occurs in two stages. The adsorption rate of the first stage is high, and in the next slower stage, the diffusion of particles is controlling stage, and the external diffusion plays an essential role in the adsorption kinetics. Langmuir isotherm best fitted to the experimental data in comparison to the Freundlich isotherm, and it could be stated that the adsorption of DAU/DOX on silica aerogels preferably follows a monolayer process. The current study revealed that adsorption using hydrophilic silica aerogel is a cost-effective process due to relatively low cost precursors and suitable alternative for removing chemotherapeutic drugs from wastewater. [ABSTRACT FROM AUTHOR]

The transfer reaction of anthracycline antibiotics, daunorubicin (DNR) and doxorubicin (DOX), was investigated at the water|1,2‐dichloroethane (DCE) interface. Spectroelectrochemical analysis demonstrated significant changes in the transfer mechanism of anthracycline cations with a slight structural difference across the bare water|DCE interface and the biomimetic interface with a phospholipid layer. The facilitated ion transfer feature was found for both HDNR+ and HDOX+ at the biomimetic interface, where the adsorption process of HDOX+ was observed over a wide potential range at the aqueous side of the interface, that is, the polar headgroup region of the phospholipid layer. The molecular association between the carboxylate‐terminated generation 3.5 polyamidoamine (G3.5 PAMAM) dendrimer and anthracycline derivatives occurred preferentially under neutral pH conditions. The negatively charged G3.5 PAMAM dendrimer induced positive shifts of the transfer potential of anthracycline cations at the water|DCE interface, indicating its ability as potential‐ and pH‐responsive drug carriers. [ABSTRACT FROM AUTHOR]

Previous studies reported that combined effect of magnetic field (MF) on cytotoxic drugs in human cancer cells. We focused on the effects of 60 Hz MF on drug activity in human uterine sarcoma MES-SA and drug-resistant variant MES-SA/Dx5 cells that overexpressed the membrane protein MDR1(P-glycoprotein), a drug efflux transporter for doxorubicin, daunorubicin, and etoposide, but not cisplatin. The cisplatin with MF caused 60% decrease in cell viability when compared with no MF treatment, cisplatin alone in MES-SA cells. Even in MES-SA/Dx5 cells, MF exposure equally enhanced cisplatin activity. Then, MF enhanced doxorubicin and daunorubicin activity in MES-SA cells and caused 60% decrease in the cell viability compared with these drugs only but had less effect on these drugs in MES-SA/Dx5 cells. Etoposide activity was unaffected by MF exposure in both cell lines, although etoposide is a MDR1 substrate as with doxorubicin and daunorubicin. Thus, MF had no direct impact on MDR1 in the cell membrane. However, the differences in doxorubicin and daunorubicin activity between MES-SA and MES-SA/Dx5 data revealed that the presence of MDR1 in abundance prevented the enhancing effects of MF on doxorubicin and daunorubicin activity. These results suggested that MF may act in the opposite direction of MDR1, affect the drug influx transporters for doxorubicin and daunorubicin, and facilitate anticancer drug uptake into the cells. [ABSTRACT FROM AUTHOR]

Abstract Background Daunorubicin is used clinically in the treatment of myeloma, acute lymphatic and myelocytic leukaemia. The toxic lesions caused by daunorubicin induce various modes of cell death, including apoptosis. Apoptosis is highly regulated programmed cell death that can be initiated mainly via two pathways, through death receptors (extrinsic) or involvement of the mitochondria (intrinsic). Induction of apoptosis via these pathways has been alluded following treatment with daunorubicin, but never compared in acute lymphoblastic leukaemia over a time course. Methods This study investigated the mechanisms of daunorubicin induced apoptosis in the treatment of CCRF-CEM, MOLT-4 (acute T-lymphoblastic leukaemia) and SUP-B15 (acute B-lymphoblastic leukaemia) cells. Cells were treated with daunorubicin for 4 h, and then placed in recovery medium (without daunorubicin) for 4 h, 12 h and 24 h. Apoptotic response was analysing using annexin-V expression, caspase activity, mitochondrial membrane potential change and an array to detect 43 apoptotic proteins. Results Daunorubicin induced apoptosis in all leukemic cell lines, but with different levels and duration of response. Both apoptosis levels and caspase activity increased after four hours recovery then declined in CCRF-CEM and MOLT-4 cells. However, SUP-B15 cells displayed initially comparable levels but remained elevated over the 24 h assessment period. Changes in mitochondrial membrane potential occurred in both MOLT-4 and CCRF-CEM cells but not in SUP-B15 cells. Expression of apoptotic proteins, including Bcl-2, Bax, caspase 3 and FADD, indicated that daunorubicin potentially induced both extrinsic and intrinsic apoptosis in both CCRF-CEM and MOLT-4 cells, but only extrinsic apoptosis in SUP-B15 cells. Conclusions This study describes variations in sensitivities and timing of apoptotic responses in different leukaemia cell lines. These differences could be attributed to the lack of functional p53 in coordinating the cells response following cytotoxic treatment with daunorubicin, which appears to delay apoptosis and utilises alternative signalling mechanisms that need to be further explored.

High interference and narrow application range are key of bottleneck of recent fluorescence analysis methods, which limit their wide application in the sensing field. Therefore, to overcome these disadvantages, a ratiometric fluorescence sensing system utilizing berberine (BER) and silver nanoclusters protected by dihydrolipoic acid (DHLA-AgNCs) was constructed for the first time in this work, to achieve determination of BER and daunorubicin (Dau). BER aqueous solution (non-planar conformation) has no fluorescence emission. When it was mixed with DHLA-AgNCs, the conformation of BER became planar, producing fluorescence emission at 515 nm besides the fluorescence emission peak of DHLA-AgNCs at 653 nm. With the increase of BER concentration added in system, the fluorescence intensity of BER (planar conformation) at 515 nm increased obviously and the fluorescence intensity of DHLA-AgNCs decreased slightly. Therefore, the dual emission fluorescence sensing system was constructed based on a fluorescence substance and non fluorescence substance, to achieve determination of BER. Meanwhile, based on the bridging effect of BER and fluorescence resonance energy transfer effect from Dau, the altering of two peaks intensity was utilized to achieve determination of Dau. Thus, this dual emission sensing system can not only be used for fluorescence analysis of BER and its analogues, but also based on the bridging effect of BER, allowing the determination of Dau and its analogues that could not be directly measured with silver nanoclusters, expanding the application range of traditional dual emission detection systems. Meanwhile, this system has strong anti-interference ability and low toxicity to the human body and less pollution to the sample and environment. This provides a new direction and universal research strategy for the construction of new fluorescence sensing systems in the future for the analysis of target substances that cannot be directly detected with conventional fluorescence analysis methods. [Display omitted] • A new ratiometric fluorescence sensing system was constructed based on DHLA-AgNCs and berberine. • The system provides a new direction for indirect fluorescence detection of target substances. • This is a convenient cascade reaction with low toxicity and little environmental pollution. • It has advantages of low time, substance cost and low environmental pollution. [ABSTRACT FROM AUTHOR]

The metabolic differences between patients with the anticancer drug daunorubicin (DRN) pose difficulties in providing clinical delivery strategies for different patients. Therefore, it is urgent to develop a pharmacokinetic platform that can real-time monitor drug levels in vivo to achieve precise drug delivery and reduce drug side effects. To this end, an electrochemical aptamer-based (E-AB) sensor was designed to realize real-time and continuous monitoring of DRN levels in vivo and obtain DRN pharmacokinetics of different individuals for the first. Specifically, the binding free energy of the aptamer to the target was calculated by molecular docking simulations. Using nanoporous gold working electrodes with immobilized aptamers as E-AB sensors, which monitored DRN in the blood of different rat models continuously for many hours with nanomolar precision and second resolution, and hundreds of DRN concentration values were obtained, based on which important pharmacokinetic parameters were simulated and computed, including half-life of drug DRN distribution and elimination, and peak concentration in blood. These parameters help to determine the metabolism of drug DRN in different patients and adjust the administered dose in time to achieve precise treatment. Therefore, this E-AB platform may provide a valuable new tool for clinicians to monitor pharmacokinetics in different patients. [Display omitted] • Nanoporous gold E-AB sensors were prepared by electrochemical alloying/alloying technique. • The determination of daunorubicin was achieved with nanomolar precision and second time resolution. • 3.The sensor can monitor the concentration of daunorubicin in blood of live rats in real time. • The sensor obtained the pharmacokinetics of daunorubicin in different rat models for the first time. [ABSTRACT FROM AUTHOR]

Drugs and pharmaceuticals are an emergent class of aquatic contaminants. The existence of these pollutants in aquatic bodies is currently raising escalating concerns because of their negative impact on the ecosystem. This study investigated the efficacy of two sorbents derived from orange peels (OP) biochar (OPBC) for the removal of the antineoplastic drug daunorubicin (DNB) from pharmaceutical wastewater. The adsorbents included pristine (OPBC) and magnetite (Fe3O4)-impregnated (MAG-OPBC) biochars. Waste-derived materials offer a sustainable and cost-effective solution to wastewater bioremediation. The results showed that impregnation with Fe3O4 altered the crystallization degree and increased the surface area from 6.99 m2/g in OPBC to 60.76 m2/g in the case of MAG-OPBC. Placket–Burman Design (PBD) was employed to conduct batch adsorption experiments. The removal efficiency of MAG-OPBC (98.51%) was higher compared to OPBC (86.46%). DNB adsorption onto OPBC followed the D–R isotherm, compared to the Langmuir isotherm in the case of MAG-OPBC. The maximum adsorption capacity (qmax) was 172.43 mg/g for MAG-OPBC and 83.75 mg/g for OPBC. The adsorption kinetics for both sorbents fitted well with the pseudo-second-order (PSO) model. The results indicate that MAG-OPBC is a promising adsorbent for treating pharmaceutical wastewater.