Deferasirox combination with eltrombopag shows anti-myelodysplastic syndrome effects by enhancing iron deprivation–related apoptosis

2021 ◽  
pp. jim-2021-002147
Author(s):  
Lei Huang ◽  
Mengyue Tian ◽  
Zhaoyun Liu ◽  
Chunyan Liu ◽  
Rong Fu
Keyword(s):  
Myelodysplastic Syndrome ◽  
Single Agent ◽  
Gene Set Enrichment Analysis ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Combination Group ◽  
Severe Thrombocytopenia ◽  
Iron Deprivation ◽  
Induced Apoptosis ◽  
Related Pathway

Iron overload (IO) affected the survival of patients with myelodysplastic syndrome (MDS). Deferasirox (DFX) is widely used in patients with MDS for iron chelation therapy, but is not suitable for MDS patients with severe thrombocytopenia. Eltrombopag (ELT) is a type of thrombopoietin receptor (TPOR) analog used in the treatment of thrombocytopenia. Therefore, we sought to explore the synergistic effects and possible mechanisms of DFX combination with ELT in MDS cells. In our study, the combination of DFX with ELT synergistically inhibited proliferation, induced apoptosis and arrested cell cycle of MDS cells. Through the RNA-sequence and gene set enrichment analysis (GSEA), iron metabolism–related pathway played important roles in apoptosis of SKM-1 cells treated with DFX plus ELT. Transferrin receptor (TFRC) was significantly highly expressed in combination group than that in single agent groups, without affecting TPOR. Furthermore, the apoptosis of the combination group MDS cells could be partially reversed by ferric ammonium citrate (FAC), accompanied with decreased expression of TFRC. These results suggested that the combination of DFX and ELT synergistically induced apoptosis of MDS cells by enhancing iron deprivation–related pathway.

Decitabine shows synergistic effects with arsenic trioxide against myelodysplastic syndrome cells via endoplasmic reticulum stress-related apoptosis

2019 ◽  
Vol 67 (7) ◽  
pp. 1067-1075 ◽  
Author(s):  
Lei Huang ◽  
Zhaoyun Liu ◽  
Huijuan Jiang ◽  
Lijuan Li ◽  
Rong Fu
Keyword(s):  
Myelodysplastic Syndrome ◽  
Er Stress ◽  
Arsenic Trioxide ◽  
Function Analysis ◽  
Synergistic Effects ◽  
Single Agent ◽  
International Prognostic Scoring System ◽  
Combination Group ◽  
Stress Related Genes ◽  
Induced Apoptosis

Most of the International Prognostic Scoring System (IPSS) high-risk patients with myelodysplastic syndrome partly responded to hypomethylating therapy even with transient remission, while arsenic trioxide (ATO) had partial effect in patients with MDS. Therefore, we sought to investigate the effects and possible mechanisms of the combination of ATO and decitabine (DAC) in MDS cells. In our study, the MUTZ-1 and SKM-1 cells were treated with ATO, DAC or both. Cell viability, cell apoptosis, levels of reactive oxygen species (ROS) and expressions of the endoplasmicreticulum (ER) stress-associated genes and proteins were examined. Results showed the combination of ATO and DAC synergistically inhibited the proliferation and induced apoptosis of MDS cells. Through the RNA-sequence and GSEA gene function analysis, ER stress-related pathway played an important role in apoptosis of MDS cells induced by the combination of ATO and DAC. ER stress-related genes DNA damage inducible transcript 3, GRP78, and activating transcription factor-6 were significantly highly expressed in combination group than those in single agent groups; proteins were confirmed by western blot. The levels of ROS significantly increased in the combination group. Furthermore, the apoptosis of (ATO+DAC) group MDS cells could be partially reversed by antioxidant agent N-acetylcysteine, accompanied by decreased expression of intracellular ROS and ER stress-related genes. These results suggested that the combination of ATO and DAC synergistically induced the apoptosis of MDS cells by increased ROS-related ER stress in MDS cells.

scholarly journals Melatonin Suppresses Iron-Induced Apoptosis by Activating the Nrf2/HO-1 Signaling Pathway in Osteoblast

2021 ◽  
Author(s):  
Hongdong Ma ◽  
Zhiqing Li ◽  
Jiao Chu ◽  
Dali Yin
Keyword(s):  
Signaling Pathway ◽  
Caspase 3 ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Oxygen Species ◽  
Apoptosis Rate ◽  
Excess Iron ◽  
Associated Proteins ◽  
Ferric Ammonium ◽  
Induced Apoptosis

Abstract Objective To investigate the effect of melatonin on the apoptosis of hFOB1.19 cells induced by excess iron. Methods The hFOB1.19 cells were treated with ferric ammonium citrate (300 μmol/L) and melatonin (100 μmol/L) for 24 h. The apoptosis rate and the level of reactive oxygen species (ROS) were analyzed using flow cytometry. Expression of proteins associated with apoptosis, such as Bax and caspase-3, and those associated with the Nrf-2 signaling pathway such as Nrf2 and HO-1 were analyzed using western blotting. Results The level of ROS and the apoptosis rate increased after intervention with excess iron. The levels of Bax in the mitochondria and cleaved caspase-3 in the cytosol increased. However, after pretreatment with melatonin, the level of ROS, apoptosis rate, and expression of apoptosis-associated proteins decreased, and the expression of Nrf2 and HO-1 increased. Conclusion Melatonin inhibits the level of oxidation in osteoblasts via the Nrf2/HO-1 signal pathway, resulting in the reduction of apoptosis induced by excess iron.

scholarly journals ATF3 contributes to brucine-triggered glioma cell ferroptosis via promotion of hydrogen peroxide and iron

2021 ◽  
Author(s):  
Shan Lu ◽  
Xuan-zhong Wang ◽  
Chuan He ◽  
Lei Wang ◽  
Shi-peng Liang ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Cell Death ◽  
Er Stress ◽  
Glioma Cell ◽  
Nuclear Translocation ◽  
Indole Alkaloid ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Activating Transcription Factor 3 ◽  
Intracellular Iron

AbstractFerroptotic cell death is characterized by iron-dependent lipid peroxidation that is initiated by ferrous iron and H2O2 via Fenton reaction, in which the role of activating transcription factor 3 (ATF3) remains elusive. Brucine is a weak alkaline indole alkaloid extracted from the seeds of Strychnos nux-vomica, which has shown potent antitumor activity against various tumors, including glioma. In this study, we showed that brucine inhibited glioma cell growth in vitro and in vivo, which was paralleled by nuclear translocation of ATF3, lipid peroxidation, and increases of iron and H2O2. Furthermore, brucine-induced lipid peroxidation was inhibited or exacerbated when intracellular iron was chelated by deferoxamine (500 μM) or improved by ferric ammonium citrate (500 μM). Suppression of lipid peroxidation with lipophilic antioxidants ferrostatin-1 (50 μM) or liproxstatin-1 (30 μM) rescued brucine-induced glioma cell death. Moreover, knockdown of ATF3 prevented brucine-induced accumulation of iron and H2O2 and glioma cell death. We revealed that brucine induced ATF3 upregulation and translocation into nuclei via activation of ER stress. ATF3 promoted brucine-induced H2O2 accumulation via upregulating NOX4 and SOD1 to generate H2O2 on one hand, and downregulating catalase and xCT to prevent H2O2 degradation on the other hand. H2O2 then contributed to brucine-triggered iron increase and transferrin receptor upregulation, as well as lipid peroxidation. This was further verified by treating glioma cells with exogenous H2O2 alone. Moreover, H2O2 reversely exacerbated brucine-induced ER stress. Taken together, ATF3 contributes to brucine-induced glioma cell ferroptosis via increasing H2O2 and iron.

scholarly journals Phase II Trial of Vorinostat With Idarubicin and Cytarabine for Patients With Newly Diagnosed Acute Myelogenous Leukemia or Myelodysplastic Syndrome

2012 ◽  
Vol 30 (18) ◽  
pp. 2204-2210 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Francesco Paolo Tambaro ◽  
Nebiyou B. Bekele ◽  
Hui Yang ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Acute Myelogenous Leukemia ◽  
Single Agent ◽  
Complete Response ◽  
Myelogenous Leukemia ◽  
Platelet Recovery ◽  
Free Survival ◽  
Binding Factor ◽  
Deacetylase Inhibitor ◽  
Acute Myelogenous

Purpose To evaluate the safety and efficacy of the combination of the histone deacetylase inhibitor vorinostat with idarubicin and ara-C (cytarabine) in patients with acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Patients and Methods Patients with previously untreated AML or higher-risk MDS age 15 to 65 years with appropriate organ function and no core-binding factor abnormality were candidates. Induction therapy was vorinostat 500 mg orally three times a day (days 1 to 3), idarubin 12 mg/m2 intravenously (IV) daily × 3 (days 4 to 6), and cytarabine 1.5 g/m2 IV as a continuous infusion daily for 3 or 4 days (days 4 to 7). Patients in remission could be treated with five cycles of consolidation therapy and up to 12 months of maintenance therapy with single-agent vorinostat. The study was designed to stop early if either excess toxicity or low probability of median event-free survival (EFS) of more than 28 weeks was likely. Results After a three-patient run-in phase, 75 patients were treated. Median age was 52 years (range, 19 to 65 years), 29 patients (39%) were cytogenetically normal, and 11 (15%) had FLT-3 internal tandem duplication (ITD). No excess vorinostat-related toxicity was observed. Induction mortality was 4%. EFS was 47 weeks (range, 3 to 134 weeks), and overall survival was 82 weeks (range, 3 to 134 weeks). Overall response rate (ORR) was 85%, including 76% complete response (CR) and 9% in CR with incomplete platelet recovery. ORR was 93% in diploid patients and 100% in FLT-3 ITD patients. Levels of NRF2 and CYBB were associated with longer survival. Conclusion The combination of vorinostat with idarubicin and cytarabine is safe and active in AML.

The management and outcomes of patients with myelodysplastic syndrome with persistent severe thrombocytopenia: An observational single centre registry study

2019 ◽  
Vol 76 ◽  
pp. 76-81 ◽  
Author(s):  
Abi Vijenthira ◽  
Devyani Premkumar ◽  
Jeannie Callum ◽  
Yulia Lin ◽  
Richard A. Wells ◽  
...  
Keyword(s):  
Myelodysplastic Syndrome ◽  
Severe Thrombocytopenia ◽  
Registry Study ◽  
Single Centre

scholarly journals An Immune Risk Score Predicts Survival of Patients with Myelodysplastic Syndrome

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 33-34
Author(s):  
Yang Liang ◽  
Fang Hu ◽  
Yu-Jun Dai ◽  
Yun Wang ◽  
Huan Li
Keyword(s):  
Regression Analysis ◽  
Myelodysplastic Syndrome ◽  
Risk Score ◽  
Prognostic Model ◽  
Validation Cohort ◽  
Gene Set Enrichment Analysis ◽  
Type I ◽  
Immune Gene ◽  
Training Cohort ◽  
Immune Score

Background: Myelodysplastic syndrome (MDS) was characterized as ineffective hematopoiesis, increased transformation to acute myeloid leukemia (AML), and accompanied by immune system dysfunction. However, the immune signature of MDS remains elusive. Methods: The clinical data (age, sex, international prognostic score system (IPSS), hemoglobin, blast, RBC transfusion dependence, and corresponding subject-level survival) as well as expression profiles of MDS (CD34+ cells) were obtained from Gene Expression Omnibus (GEO: GSE 58831; GSE 114922). A robust prognosis model of immune genes was constructed by the least absolute shrinkage and selection operator (LASSO) regression analysis. Survival analysis for prognostic model was carried out through the Kaplan-Meier curve and Log-rank test. The receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to assess the accuracy of prognostic models. Immune score for different subtype were calculated further by single sample gene set enrichment analysis (ssGSEA). Result: A novel robust immune gene prognostic model indicate that subtype with lower risk score were longer overall survival (OS) than subtype with higher risk score in training cohort (Figure1 A, C). The model was further verified by the validation cohort (Figure1 B, D). The multivariate Cox regression analysis demonstrated the model was an independent prognostic factor for OS prediction with hazard ratios of 56.694 (95% CIs: 9.038−355.648), 3.009 (95% CIs: 1.042−8.692) both in train cohort and external validation cohort respectively (Figure1 G, H). The AUC of 5- year were 0.92 (95% CIs: 0.86 - 0.97) and 0.7 (95% CIs: 0.51 - 0.89) for OS respectively in training cohort and validation cohort (Figure1 E, F). Furthermore, ssGSEA showed higher risk score subtype was significantly associated with higher immune score of check point, human leukocyte antigen (HLA), T cell co-inhibition and type I interferon (IFN) response (Figure1 K-N), which indicating that the poor outcome might be caused by tumor-associated immune response dysfunction partly. Conclusion: We constructed a robust immune gene prognostic model, which have a potential prognostic value for MDS patients and may provide evidence for personalized immunotherapy. Figure Disclosures No relevant conflicts of interest to declare.

scholarly journals A study on the aspects of pharmacoepidemiology and pharmacohaemovigilance of ferrous ascorbate, ferrous fumarate, ferrous sulphate and ferric ammonium citrate, among the rural anaemic women, in the Indian spectrum

2019 ◽  
Vol 8 (12) ◽  
pp. 2751
Author(s):  
Moumita Hazra
Keyword(s):  
Ferrous Sulphate ◽  
Haemoglobin Concentration ◽  
Significant Rise ◽  
Demographic Characteristics ◽  
Health Concern ◽  
Ammonium Citrate ◽  
Ferric Ammonium Citrate ◽  
Ferrous Fumarate ◽  
Ferrous Ascorbate ◽  
Ferric Ammonium

Background: Anaemia is a global health concern, associated with increased maternal and perinatal mortality, preterm delivery, low birth weight, extreme fatigue and impaired immune system; and controlled by oral haematinics; with a rise in haemoglobin concentration. The objective was to examine the various aspects of pharmacoepidemiology and pharmacohaemovigilance of oral haematinics, among the anaemic women population, in rural India.Methods: This was a multi-centre, retrospective, observational and analytical study of the hospital medical records of 250 anaemic patients, who were allocated into group A of 125 patients within 15-21 years and group B of 125 patients within 22-35 years. The patients were prescribed oral haematinics, containing 60 mg of elemental iron, thrice daily, with meals. The various aspects of pharmacoepidemiology and pharmacohaemovigilance of ferrous ascorbate, ferrous sulphate, ferrous fumarate and ferric ammonium citrate, including patients’ demographic characteristics, anaemic symptoms assessment, prescription patterns, and safety assessment, on 1st, 2nd, 3rd months and follow-up visits, were recorded and thoroughly analysed..Results: In groups A and B, the demographic characteristics of the patients were comparable; ferrous ascorbate was the most commonly prescribed oral haematinic, followed by ferrous sulphate, ferrous fumarate and ferric ammonium citrate, which controlled mild to moderate iron deficiency anaemia, with a gradual significant rise in haemoglobin concentration, in the successive 3 months; and adverse effects were observed to be statistically non-significant in either group.Conclusions: The different aspects of pharmacoepidemiology and pharmacohaemovigilance in the study established that the oral haematinics were reasonably beneficial and safe among the anaemic women population, in rural India.

scholarly journals Development and pre-clinical testing of a novel hypoxia-activated KDAC inhibitor

2021 ◽  
Author(s):  
Anna Skwarska ◽  
Ewen Calder ◽  
Deborah Sneddon ◽  
Hannah Bolland ◽  
Maria Odyniec ◽  
...  
Keyword(s):  
Single Agent ◽  
Tumor Hypoxia ◽  
Clonogenic Survival ◽  
Therapy Resistance ◽  
Growth Delay ◽  
Pharmacokinetic Analysis ◽  
Lysine Deacetylase ◽  
Oxygen Conditions ◽  
Patient Prognosis ◽  
Induced Apoptosis

Tumor hypoxia is associated with therapy resistance and poor patient prognosis. Hypoxia-activated prodrugs, designed to selectively target hypoxic cells while sparing normal tissue, represent a promising treatment strategy. We report the pre-clinical efficacy of 1-methyl-2-nitroimidazole panobinostat (NI-Pano, CH-03), a novel bioreductive version of the clinically used lysine deacetylase inhibitor, panobinostat. NI-Pano was stable in normoxic (21% oxygen) conditions and underwent NADPH-CYP-mediated enzymatic bioreduction to release panobinostat in hypoxia (<0.1% oxygen). Treatment of cells grown in both 2D and 3D with NI-Pano increased acetylation of histone H3 at lysine 9, induced apoptosis and decreased clonogenic survival. Importantly, NI-Pano exhibited growth delay effects as a single agent in tumor xenografts. Pharmacokinetic analysis confirmed the presence of sub- micromolar concentrations of panobinostat in hypoxic mouse xenografts, but not in circulating plasma or kidneys. Together, our preclinical results provide a strong mechanistic rationale for the clinical development of NI-Pano for selective targeting of hypoxic tumors.<br>

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