scholarly journals Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Ho-Min Yu ◽  
Do Kyoung Kim ◽  
Hye Jin Seo ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Leukemia Cell ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Distribution ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. Methods Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. Results The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

scholarly journals Radotinib enhances cytarabine (Ara-C)-induced acute myeloid leukemia cell death

2020 ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Ho-Min Yu ◽  
Do Kyoung Kim ◽  
Hye Jin Seo ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Combined Treatment ◽  
Leukemia Cell ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Distribution ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death in AML cells. Therefore, we investigated combination effects of radotinib and Ara-C on AML in this study. Methods: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. Results: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C , and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G 0 /G 1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G 0 /G 1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo . Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

scholarly journals Radotinib Enhances Cytarabine (Ara-C)-Induced Acute Myeloid Leukemia Cell Death

2020 ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Ho-Min Yu ◽  
Do Kyoung Kim ◽  
Hye Jin Seo ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Annexin V ◽  
Chemotherapeutic Agents ◽  
Cell Cycle Distribution ◽  
Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is a heterogeneous disease that frequently relapses after standard chemotherapy. Therefore, there is a need for the development of novel chemotherapeutic agents that could treat AML effectively. Radotinib, an oral BCR-ABL tyrosine kinase inhibitor, was developed as a drug for the treatment of chronic myeloid leukemia. Previously, we reported that radotinib exerts increased cytotoxic effects towards AML cells. However, little is known about the effects of combining radotinib with Ara-C, a conventional chemotherapeutic agent for AML, with respect to cell death and cell cycle distribution in AML cells. Methods: Synergistic anti-cancer effects of radotinib and Ara-C in AML cells including HL60, HEL92.1.7, THP-1 and bone marrow cells from AML patients have been examined. Diverse cell biological assays such as cell viability assay, Annexin V-positive cells, caspase-3 activity, cell cycle distribution, and related signaling pathway have been performed. We also confirmed synergistic effects of radotinib and Ara-C on the xenograft model in vivo. Results: The combination of radotinib and Ara-C was found to induce AML cell apoptosis, which involved the mitochondrial pathway. In brief, combined radotinib and Ara-C significantly induced Annexin V-positive cells, cytosolic cytochrome C, and the pro-apoptotic protein Bax in AML cells including HL60, HEL92.1.7, and THP-1. In addition, mitochondrial membrane potential and Bcl-xl protein were markedly decreased by radotinib and Ara-C. Moreover, this combination induced caspase-3 activity. Cleaved caspase-3, 7, and 9 levels were also increased by combined radotinib and Ara-C. Additionally, radotinib and Ara-C co-treatment induced G0/G1 arrest via the induction of CDKIs such as p21 and p27 and the inhibition of CDK2 and cyclin E. Thus, radotinib/Ara-C induces mitochondrial-dependent apoptosis and G0/G1 arrest via the regulation of the CDKI–CDK–cyclin cascade in AML cells. In addition, our results showed that combined treatment with radotinib and Ara-C inhibits AML cell growth, including tumor volumes and weights in vivo. Also, the combination of radotinib and Ara-C can sensitize cells to chemotherapeutic agents such as daunorubicin or idarubicin in AML cells. Conclusions: Therefore, our results can be concluded that radotinib in combination with Ara-C possesses a strong anti-AML activity.

scholarly journals Author Correction: Targeting c-KIT (CD117) by dasatinib and radotinib promotes acute myeloid leukemia cell death

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sook-Kyoung Heo ◽  
Eui-Kyu Noh ◽  
Jeong Yi Kim ◽  
Yoo Kyung Jeong ◽  
Jae-Cheol Jo ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Acute Myeloid Leukemia Cell ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

scholarly journals Addition of PTK787/ZK 222584 can lower the dosage of amsacrine to achieve equal amounts of acute myeloid leukemia cell death

2008 ◽  
Vol 19 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Alida C. Weidenaar ◽  
Hendrik J.M. de Jonge ◽  
Vaclav Fidler ◽  
Arja ter Elst ◽  
Tiny Meeuwsen-de Boer ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Acute Myeloid Leukemia Cell ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Anti-Acute Myeloid Leukemia Activity of Chaetocin, a Novel Epigenetic Drug Inhibitor Inducing Oxidative Stress.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 889-889
Author(s):  
Hassiba Chaib ◽  
Thomas Prebet ◽  
Audrey Restouin ◽  
Remy Castellano ◽  
Sandrine Opi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Caspase 3 ◽  
Hdac Inhibitors ◽  
Oxidative Species ◽  
Acute Myeloid

Abstract Recent studies have highlighted the importance of epigenetic modifications in the pathogenesis of Acute Myeloid Leukemia (AML). This results have been confirmed by the activity of new drug like DNA demethylating agents and histone deacetylase (HDAC) inhibitors in both in vivo and in vitro studies. Recently, Chaetocin, a natural fungal compound, has been identified as the first specific inhibitor of the histone methyltransferase SU(VAR)3–9 which plays a role in heterochromatin gene silencing. In this study, we decided to evaluate Chaetocin as a therapeutic agent in AML in vitro and to explore the related mechanisms. We show that Chaetocin induce dramatic cell death at nanomolar concentrations in U937 and HL60 (97.2% ± 0.4 and 91.6% ± 9 cell death at 100 nM chaetocin, respectively), and to a lesser extend in K562 (67.3% ± 1.6 cell death at 100 nM chaetocin), cell cultures. Cell death occurred at 24 h incubation time which correlated with induction of apoptosis as assessed by Annexin V/7-AAD staining and activation of downstream executioner caspase-3/7. Using transcription low-density array and quantitative RT- PCR, Chaetocin was showed to up-regulate gene transcription such as of the cell cycle inhibitor p21/WAF1 consistent with a role for the targeted SU(VAR)3–9 in heterochromatin gene silencing. In agreement with the recent report of Chaetocin being a promising new antimyeloma agent acting via imposition of oxidative stress, intracellular levels of oxidative species were increased in Chaetocin treated U937 cells in a time- and dose-dependent manner that correlated with induction of cell death. Furthermore, incubation of cells with N-acetyl cysteine, a cell-permeable precursor of intracellular glutathione reductant, prevented chaetocin-induced accumulation of oxidative species, transcription of selected genes (e.g. p21/WAF1), activation of caspase-3, and cell death. Finally, Chaetocin was found to increase the antileukemia activity of HDAC inhibitors and Aracytin, and thus appears as a promising agent for further study as a potential anti-AML therapeutic. Preliminary results obtained in vivo in xenograft models and ex vivo, using blasts of a panel of patients with AML, will be presented.

VLA4 Blockade In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3944-3944 ◽  
Author(s):  
Yao-Te Hsieh ◽  
Enzi Jiang ◽  
Jennifer Pham ◽  
Hye-Na Kim ◽  
Hisham Abdel-Azim ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Leukemia Cell ◽  
Chemotherapeutic Agents ◽  
Bone Marrow Stroma ◽  
Nsg Mice ◽  
Marrow Stroma ◽  
Acute Myeloid

Abstract Despite aggressive chemotherapy and early allogeneic transplantation, acute myeloid leukemia (AML) frequently relapses, so that over-all disease-free survival remains below 50%. Strategies to overcome the chemoresistance of relapse-initiating residual AML blasts are, therefore, warranted. Evidence has been provided that AML cells are sheltered from the insult of chemotherapeutic agents by interacting with bone marrow stroma. Integrin alpha4beta1 (VLA4) mediates adhesion of hematopoietic cells to bone marrow stroma cells and extracellular matrix and has been implicated in cell adhesion-mediated chemotherapy resistance. Based on the evidence thereof provided for ALL blasts, VLA4 is here proposed as a therapeutic target for refractory AML. For this purpose, VLA4 was functionally blocked in vitro and in vivo on patient-derived AML cells using an anti-functional humanized VLA4 antibody, Natalizumab (NZM). VLA4-positive (>90%) patient-derived (primary) AML cells were plated on immobilized human VCAM1 or human stromal cell line HS-5 and treated with control (IgG4) or Natalizumab (NZM) for 2 days. NZM de-adhered 94.0%±7.6 AML cells from its counter receptor VCAM-1, yet only 31.3%±13.8 from HS-5, indicating that stroma cells offer ligands for a wider panel of adhesion receptors besides VLA4. We tested also whether VLA4 blockade is beneficial against AML when combined with chemotherapy. For this purpose, primary AML cells were incubated with NZM and incubated on uncoated tissue culture plates or HS-5 stromal layers in the presence or absence of Ara-C (1µM) for two days. AML cells showed higher viability under Ara-C therapy when incubated with HS-5 cells compared to controls, indicating the chemoprotective effect of the stromal layer. The viability of the AML cells treated with combined Ara-C and NZM was similar to the controls, indicating that HS-5-mediated chemo-protection was completely abrogated by NZM. Significantly more AML cells treated with Ara-C+NZM stained AnnexinV+/7AAD- than after Ara-C+control Ig4 treatment (44.4%±5.6 vs. 29.8%±4.8, p=0.03) indicating increased apoptosis of AML cells. On its own, NZM did not induce apoptosis. Next, we tested NZM as a single agent in our NOD/SCIDIL2Rγ deficient (NSG) xenograft model of primary AML. Luciferase-labeled AML cells were intrafemorally injected into NSG mice (1x105 cells / mouse). NZM (5mg/kg) was given intraperitoneally once per week for 4 weeks. NZM-treated animals survived significantly longer than control Ig-treated animals (Median Survival Time, MST=107 days vs. MST=76 days; *p=0.008 by Log-rank Test.To determine effects of NZM on leukemia cell burden/distribution in different organs, primary AML cells were injected into NSG mice and allowed to engraft for 3 days, subsequently treated with a single dose of NZM or Ig control. 72 hours later, AML cell burden in femurs and spleens of NZM-treated animals was significantly decreased compared to control treated mice, however AML cells were not increased into the peripheral blood, so that whether leukemia cells were selectively killed ormobilized and then retained in non-hematopoietic organs remains to be determined. Further studies addressing molecular mechanisms of increased apoptosis after combined VLA4 blockade and chemotherapy are ongoing. Our data suggest that the paradigm of leukemia cell targeting by VLA4 blockade, previously demonstrated by us for ALL, can also be applied to AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Docosahexanoic acid induces dose dependent cell death in an early undifferentiated subtype of acute myeloid leukemia cell line

2009 ◽  
Vol 8 (4) ◽  
pp. 331-337 ◽  
Author(s):  
Takashi Yamagami ◽  
Christopher D Porada ◽  
Ronald Pardini ◽  
Esmail D Zanjani ◽  
Graca D Almeida-Porada
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Leukemia Cell Line ◽  
Docosahexanoic Acid ◽  
Dependent Cell ◽  
Dose Dependent ◽  
Acute Myeloid ◽  
Myeloid Leukemia Cell

Acute Myeloid Leukemia Cells Depend on VEGF, PDGFR and SCF Receptor Signaling: Leukemia Regression with Pazopanib.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1057-1057 ◽  
Author(s):  
Eric Gars ◽  
Christie S McGee ◽  
Raphael C Bosse ◽  
Elizabeth Wise ◽  
Amy Meacham ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Endothelial Cells ◽  
Acute Myeloid Leukemia ◽  
Growth Factors ◽  
Growth Factor ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Annexin V ◽  
Leukemia Cells ◽  
Acute Myeloid

Abstract Abstract 1057 Acute myeloid leukemia (AML) cells depend on endothelial cells for survival and proliferation. By targeting endothelial cells with a novel vascular disrupting agent, we recently demonstrated regression of AML (Madlambayan, et al., Blood 2010). In an effort to discover a more selective, anti-vascular therapy for leukemia, we hypothesized that targeting endothelial cell-derived paracrine and leukemia cell-derived autocrine growth factors would result in regression of disease. In particular, our strategy focused on vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF) and stem cell factor (SCF), which are known to promote leukemia cell proliferation. Receptors for each of these growth factors are potently inhibited by pazopanib, which is an orally available tyrosine kinase inhibitor. The aim of our study was to determine the dependence of leukemia cell survival and proliferation on the combined receptor signaling of VEGF, PDGF and SCF. Leukemia cell lines (KG-1, HL60 and K562) were incubated at various durations with varying concentrations of pazopanib. Leukemia cell proliferation was quantified using XTT assay. Apoptosis induction was analysed by flow cytometry (Annexin V and PI staining). Pazopanib effectively impaired proliferation in leukemia cells in vitro in a dose and time dependent fashion. During a 16-hour incubation of leukemia cells, pazopanib showed a 50% lethal concentration (LC50) of 22.57 μM (r = .986), 41.6 μM (r = .991), and 81.97 μM (r = .996) for HL60, K562, and KG-1 cells, respectively. Staining with Annexin V and PI identified apoptosis as the main cause of cell death after exposure to pazopanib. The IC50 of apoptosis for HL60 cells was 132.5 ± 2.7 μM (p = 0.0002). These results indicate that leukemia cells depend on the combined signaling of VEGF, PDGF, and SCF, and suggest that selective inhibition by pazopanib may be a promising therapeutic for AML. Furthermore, pazopanib is orally available and associated with minimal side effects, thus representing an attractive candidate for further testing in AML. Disclosures: No relevant conflicts of interest to declare.

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