scholarly journals High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3091-3096 ◽  
Author(s):  
L Campos ◽  
JP Rouault ◽  
O Sabido ◽  
P Oriol ◽  
N Roubi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Protein ◽  
High Expression ◽  
Leukemic Cells ◽  
Stem Cell Marker ◽  
Cell Counts ◽  
Response To Chemotherapy ◽  
Acute Myeloid

The BCL-2 proto-oncogene encodes a mitochondrial protein that blocks programmed cell death. High amounts of bcl-2 protein are found not only in lymphoid malignancies, but also in normal tissues characterized by apoptotic cell death, including bone marrow. Using a monoclonal antibody to bcl-2 protein, we analyzed 82 samples of newly diagnosed acute myeloid leukemia. The number of bcl-2+ cells in each sample was heterogeneous (range, 0% to 95%), with a mean of 23%. The percentage of bcl-2+ cells was higher in M4 and M5 types, according to French- American-British classification, and in cases with high white blood cell counts. bcl-2 expression was also correlated with that of the stem cell marker CD34. In vitro survival of leukemic cells maintained in liquid culture in the absence of growth factors was significantly longer in cases with a high percentage of bcl-2+ cells. High expression of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (29% in cases with 20% or more positive cells v 85% in cases with less than 20% positive cells, P < 10(-5)) and with a significantly shorter survival. In multivariate analysis, the percentage of bcl-2+ cells (or the blast survival in culture), age, and the percentage of CD34+ cells were independently associated with poor survival.

scholarly journals High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3091-3096 ◽  
Author(s):  
L Campos ◽  
JP Rouault ◽  
O Sabido ◽  
P Oriol ◽  
N Roubi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Protein ◽  
High Expression ◽  
Leukemic Cells ◽  
Stem Cell Marker ◽  
Cell Counts ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Abstract The BCL-2 proto-oncogene encodes a mitochondrial protein that blocks programmed cell death. High amounts of bcl-2 protein are found not only in lymphoid malignancies, but also in normal tissues characterized by apoptotic cell death, including bone marrow. Using a monoclonal antibody to bcl-2 protein, we analyzed 82 samples of newly diagnosed acute myeloid leukemia. The number of bcl-2+ cells in each sample was heterogeneous (range, 0% to 95%), with a mean of 23%. The percentage of bcl-2+ cells was higher in M4 and M5 types, according to French- American-British classification, and in cases with high white blood cell counts. bcl-2 expression was also correlated with that of the stem cell marker CD34. In vitro survival of leukemic cells maintained in liquid culture in the absence of growth factors was significantly longer in cases with a high percentage of bcl-2+ cells. High expression of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (29% in cases with 20% or more positive cells v 85% in cases with less than 20% positive cells, P < 10(-5)) and with a significantly shorter survival. In multivariate analysis, the percentage of bcl-2+ cells (or the blast survival in culture), age, and the percentage of CD34+ cells were independently associated with poor survival.

scholarly journals P2X7 Receptor Activation By ATP As Target of Novel Therapies in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3684-3684
Author(s):  
Valentina Salvestrini ◽  
Stefania Orecchioni ◽  
Francesca Reggiani ◽  
Giovanna Talarico ◽  
Elisa Orioli ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Pore Formation ◽  
Cytotoxic Effect ◽  
Leukemic Cells ◽  
Cell Compartment ◽  
Hematopoietic Stem ◽  
Direct Cytotoxicity ◽  
Acute Myeloid

Abstract ATP is the key energy molecule as well as an ubiquitous extracellular messenger. Depending on its dose and the engaged purinergic P2 receptor (P2R) subtype, ATP can trigger many different cell responses, including proliferation and cell death. Recent studies have shown that high ATP level exhibits direct cytotoxicity on many tumor cell types. Among the receptors engaged by ATP, P2X7 is the most consistently expressed by tumor cells and its overexpression is related to tumor growth and progression. The P2X7 is an ATP-gated ion channel that, upon sustained stimulation with millimolar ATP concentrations, drives the opening of a non-selective large conductance pore, triggering cell-death signal. We previously demonstrated that ATP is a potent stimulator of normal hematopoietic stem cell compartment while inhibiting acute myeloid leukemia (AML) cells. Based on this observation, we studied AML samples (n=20) collected from the bone marrow or the peripheral blood of leukemic patients at diagnosis before treatment (percentage of circulating blasts >90%). In addition, normal hematopoietic stem cells (HSC) were isolated from leukapheresis products of 5 healthy donors receiving G-CSF. Our data demonstrate that AML cells express high level of P2X7 and that its activation with high dose of ATP reduces blast cell viability while is not effective on normal CD34+ cells. The cytotoxic effect is due to the induction of apoptosis, associated with reduction of mithocondrial membrane potential and activation of caspase cascade. Interestingly, P2X7 is also expressed by leukemic stem/progenitor cells (LSC) and ATP treatment exerts a direct cytotoxicity on different subsets of stem/progenitor cell compartment i.e. CD34- CD38-, CD34+ CD38-, CD34+ CD38+ and CD34- CD38+. Of note, this cytotoxic effect was not observed on HSC subpopulations. Furthermore, we transplanted 1x106 human AML cells into NSG immunodeficient mice followed by intraperitoneal administration of ATP every other day for thirty days post-transplantation. Our results show a 40% inhibition of AML engraftment in ATP-treated mice vs controls. Different P2X7 splice variants have been identified among which only two are functional: P2X7A, which shows both pro-apoptotic and trophic activity and P2X7B, which retains only the growth promoting phenotype. In order to explain ATP different effects on LSCs and normal HSCs, we assumed a different P2X7 isoforms expression on normal and leukemic cells. Preliminary results showed a reduced expression of both P2X7A and P2X7B on normal CD34+ compared to leukemic cells. In particular normal CD34+ express very low level of P2X7A, which is responsible for pore formation after ATP stimulation. Moreover, since P2X7 pore formation facilitates the passage of hydrophilic chemotherapeutic agents, we hypothesized that ATP may potentiate the cytotoxic effect of antineoplastic drugs. Our results showed that ATP potentiates the cytotoxic effect of ARA-C, by significantly reducing cell proliferation and increasing apoptosis of leukemia cell lines. In conclusion, overall survival of adult AML remains poor due to the lack of novel and effective therapies. Novel compounds that have the potential to improve the treatment efficacy with low toxicity are highly warranted. Overall, our results may provide the biological rationale to use P2X7 as a target for novel therapeutical approaches against AML. Disclosures Cavo: Janssen-Cilag, Celgene, Amgen, BMS: Honoraria.

scholarly journals Impact of Bone Marrow miR-21 Expression on Acute Myeloid Leukemia T Lymphocyte Fragility and Dysfunction

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2053
Author(s):  
Douâa Moussa Agha ◽  
Redouane Rouas ◽  
Mehdi Najar ◽  
Fatima Bouhtit ◽  
Hussein Fayyad-Kazan ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Myeloid Leukemia ◽  
Myeloid Cell ◽  
Leukemic Cells ◽  
Hematopoietic Malignancy ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy in which antitumor immunity is impaired. The therapeutic management of AML requires understanding the mechanisms involved in the fragility and immune dysfunction of AML T lymphocytes. Methods: In this study, T lymphocytes from healthy donors (HD) and AML patients were used. Extracellular vesicles (EVs) from leukemic cells were screened for their microRNA content and impact on T lymphocytes. Flow cytometry, transcriptomic as well as lentiviral transduction techniques were used to carry out the research. Results: We observed increased cell death of T lymphocytes from AML patients. EVs from leukemia myeloid cell lines harbored several miRNAs, including miR-21, and were able to induce T lymphocyte death. Compared to that in HD, miR-21 was overexpressed in both the bone marrow fluid and infiltrating T lymphocytes of AML patients. MiR-21 induces T lymphocyte cell death by upregulating proapoptotic gene expression. It also increases the immunosuppressive profile of T lymphocytes by upregulating the IL13, IL4, IL10, and FoxP3 genes. Conclusions: Our results demonstrate that miR-21 plays a significant role in AML T lymphocyte dysfunction and apoptosis. Targeting miR-21 may be a novel approach to restore the efficacy of the immune response against AML.

Influence of High Expression of p73 and p53 Proteins on Clinical Outcome in Acute Myeloid Leukemia Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4306-4306
Author(s):  
Agnieszka Pluta ◽  
Piotr Smolewski ◽  
Agnieszka Wierzbowska ◽  
Barbara Cebula ◽  
Krzysztof Jamroziak ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Induction Chemotherapy ◽  
Myeloid Leukemia ◽  
High Expression ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Spontaneous Apoptosis ◽  
Acute Myeloid

Abstract Background: Prognostic significance of apoptosis-regulating proteins, especially p73, is not clearly determined in acute myeloid leukemia (AML). The p73 protein is a member of p53 family implicated in the regulation of cell cycle, apoptosis and development. Overexpression of p73 protein, with prevalence of short TAp73 isoforms, has recently been described in patients with AML. Aims: The main objective of this study was to verify whether expression of p73 and p53 proteins has a prognostic impact on response to induction chemotherapy and overall survival (OS) of adult patients with AML. Additionally, we aimed to correlate the expression of p73 and p53 proteins with spontaneous apoptosis of leukemic cells. Material and Methods: Intracellular expression of p73 protein in leukemic blasts isolated from bone marrow or peripheral blood was examined in 73 AML patients (59 de novo, 14 refractory/relapsed) of median age 54 years (range 28–78 years). In parallel, analysis of cell cycle in leukemic blasts was performed to assess the subG1 fraction as a marker of spontaneous apoptosis. The control constituted leukemic cells incubated with isotype antibodies. All measurements were performed using multi-colour flow cytometry. Protein expression was expressed by both percentage of positive cells and mean fluorescence intensity. Results: Fifty six patients received intensive induction chemotherapy. Twenty four (43%) patients achieved complete response (CR), 26 (46%) patients did not respond and 6 (11%) patients died in the early post-induction period. The median time of follow up reached 5.6 months (range 0.1–99 months). High expression of p73 showed a trend towards probability of CR achievement after induction regimen (p=0.08). Higher expression of p53 did not correlate with response to the treatment (p=0.28). In univariate analysis we found significantly better OS in patients less than 60 years old, with good or intermediate risk of kariotype and treated with intensive chemotherapy (p=0.00001; p=0.04; p=0.00001, respectively). Probability of better OS in AML patients with high p73 and p53 protein expression was p=0.1 and p=0.95, respectively. Simultaneous high expression of both p73 and p53 proteins on AML cell showed a trend toward longer OS (p=0.09). Moreover, a strong trend to better OS was observed in patients with high subG1 fraction. Importantly, high subG1 fraction correlated with high expression of p53 but not with p73 protein expression (p=0.03; p=0.15, respectively). Conclusions: These data indicate that p73 protein may be implicated in apoptosis of AML in response to chemotherapy, especially when p53 pathway is abrogated. Further studies are needed to establish exact role of p73 and p53 proteins in this process and its influence on OS of AML patients.

CXCR4 as a Predictor of Response in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2941-2941
Author(s):  
Domenico Pastore ◽  
Anna Mestice ◽  
Margherita Giannoccaro ◽  
Arcangelo Liso ◽  
Maria Paola Martelli ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Negative Regulator ◽  
Leukemic Cells ◽  
Common Mutation ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract The expression of CXCR4 (CD184) has been associated with poor prognosis in Acute Myeloid Leukemia (AML) and it has also been suggested that the CXCL12(SDF-1a)/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Inhibition of CXCR4 was found to enhance chemotherapy-induced apoptosis in a subset of leukemic myeloblasts that carry Flt3 mutations and to overcome chemoresistance associated with stromal activity. NPM variants with a cytoplasmic localization represent the most common mutation detected in myeloid malignancies and are associated with a favourable clinical outcome. A recent study provides biological evidence for a novel role for NPM as a negative regulator of CXCR4 signalling induced by CXCL12: suppression of NPM expression enhanced chemotactic responses to CXCL12, and conversely, over-expression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. We investigated whether CD184 expression is a negative predictor factor for response to chemotherapy and if there is clinical evidence that NPM mutations could overcome chemoresistance to induction therapy in this subset of patients. The expression of CD184 was analyzed by flow cytometric methods in a group of 70 cases of adult AML at onset of disease, diagnosed at our Institution since January 2006. The diagnosis was performed according to FAB/WHO criteria; all patients received intensive chemotherapy according to institutional protocols. There were 34 males and 36 females and median age was 46 years (range 18–65). AML cells were gated based upon their CD45 expression and samples were considered positive if CD184 was expressed by more than 20% of blasts. CD184 was positive in 45 and negative in 25 cases. There was no significant difference between the two groups in terms of sex, age, Hb level, WBC and Plt counts, percentage of blasts, and occurrence of the NPM mutation. The CR rate was 45% in CD184+ and 82% in CD184- (p=0.03); among CD184+ cases, the CR rate was significantly higher in NPMc+ cases, (p=0.03). Our results show that CD184 expression is associated with a lower rate of CR after induction therapy and this association is stronger in NPM unmutated cases, suggesting that CD184 expression is a negative predictive factor for response to chemotherapy. Further data are needed to verify if the biological role of the cytosolic NPM mutant as a negative regulator of CXCR4 signalling induced by CXCL12 could have a clinical role contributing to overcome the resistance of leukemic cells to induction chemotherapy.

Expression Of FLT3-ITD Dysregulates The DBC1-Sirt1-p53 Signaling and Promotes Therapy Resistance

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3789-3789
Author(s):  
Daniel Sasca ◽  
Patricia Haehnel ◽  
Kaml I.K. Khawaja ◽  
Birgit Enders ◽  
Lars Bullinger ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Expression Analysis ◽  
Myeloid Leukemia ◽  
Cell Activity ◽  
Leukemic Cells ◽  
Genotoxic Agents ◽  
Acute Myeloid

Abstract Background SIRT1 is a NAD+ dependent histone deacetylase, which has been shown to act as an important regulator of apoptosis, DNA-repair and is involved in the maintenance of genetic integrity under conditions of cellular stress. Beside deacetylation of histones H4K16, SIRT1 has numeral other substrates including KU70, FOXO1 or p53. SIRT1 deacetylates p53 at lysine 382 thereby reducing its transcriptional activity followed by loss of p53 dependent apoptosis in response to cell damage. The activity of SIRT1 is negatively regulated by DBC1 (Deleted in Breast Cancer 1) and involves protein–protein interaction (Kim et al., Nature 2008). Recent reports have demonstrated increased expression of SIRT1 in leukemic cells. Of note, SIRT1 seems to be specifically essential to maintain stem cell activity in CML leukemic stem cells (Li et al, Cancer Cell, 2012), however the role of SIRT1 in acute myeloid leukemia (AML) and in the context of other oncogenic tyrosine kinases is poorly understood. Aims To characterize the role of SIRT1 in acute myeloid leukemia in the context of defined genetic backgrounds. Methods To investigate the functional role of SIRT1 we performed expression analysis studies. Inhibition of SIRT1 was achieved by shRNA experiments and pharmacological targeting. Functional consequences were addressed by immunoblotting, co-immunoprecipitation, cell death assays, gamma-H2AX staining and xenotransplantion experiments. Results SIRT1 protein expression analysis in primary human AML samples (n=20) and cell lines (n=13) showed preferential high expression levels in cells harboring FLT3-ITD mutations or oncogenic KRAS/NRAS. Inhibition of FLT3 signaling using shRNA-mediated knockdown of FLT3 or upon treatment with tyrosine kinase inhibitors caused a time and dose dependent suppression of SIRT1 expression accompanied by an increase in p53 acetylation. Vice versa, overexpression of FLT3-ITD in BaF/3 cells or in several murine leukemia models (e.g. MLL/AF9 +/-FLT3-ITD; AML1/ETO +/-FLT3-ITD) induced significant upregulation of SIRT1. Targeting SIRT1 using the SIRT1/2 inhibitor Tenovin-6 (TV-6) or knockdown of SIRT1 resulted in a slight increase in apoptotic cell death in primary AML samples and cell lines. In contrast, inhibition of SIRT1 significantly sensitized to FLT3 inhibitor therapy. Of note, the combination of TV-6 and midostaurin inhibited colony growth and replating activity in MLL-AF9 or AML1-ETO cells harboring FLT3-ITD mutations. Further, knockdown of SIRT1 in the AML cell line MV4-11 expressing a doxycycline-regulated SIRT-shRNA resulted in prolonged survival in a xenotransplantation model. The observed effects prompted us to investigate whether mutated FLT3 is directly involved in the regulation of SIRT1. Inhibition of FLT3-ITD kinase activity caused an increased phosphorylation of the physiological SIRT1-inhibitor DBC1 followed by binding of SIRT1 as revealed by co-immunoprecipitation experiments. We also noticed a slight increase in ATM/ATR phosphorylation and an increase in ATM-DBC1 binding upon FLT3-ITD inhibition indicating SIRT1 inhibition via the ATM-DBC1-SIRT1 axis. These effects were substantially enhanced upon treatment with genotoxic agents (cytarabine; irradiation) in combination with midostaurin compared to either agent alone and were accompanied by increased p53 acetylation and an increased number of gamma-H2AX foci. Conclusion SIRT1 is overexpressed in AML cells and partially regulated by FLT3-ITD or oncogenic RAS. In FLT3-ITD mutated cells SIRT1 is constitutively activated, likely via the inhibition of the physiological inhibitor DBC1. Pharmacologic targeting of SIRT1 sensitizes AML cells to TKI therapy or genotoxic agents and partially restored the FLT3-ITD associated defective stress response pathway ATM-DBC1-SIRT1 resulting in activation of p53. Disclosures: Kindler: Novartis: Membership on an entity’s Board of Directors or advisory committees.

scholarly journals Rationale for a Combination Therapy with the STAT5 Inhibitor AC-4-130 and the MCL1 Inhibitor S63845 in the Treatment of FLT3-Mutated or TET2-Mutated Acute Myeloid Leukemia

2021 ◽  
Vol 22 (15) ◽  
pp. 8092
Author(s):  
Katja Seipel ◽  
Carolyn Graber ◽  
Laura Flückiger ◽  
Ulrike Bacher ◽  
Thomas Pabst
Keyword(s):  
Bone Marrow ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Map Kinases ◽  
Leukemic Cells ◽  
Bone Marrow Stroma ◽  
Flt3 Inhibitors ◽  
Marrow Stroma ◽  
Acute Myeloid

The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with de novo acute myeloid leukemia (AML). Mutated FLT3 variants are constitutively active kinases signaling via AKT kinase, MAP kinases, and STAT5. FLT3 inhibitors have been approved for the treatment of FLT3-mutated AML. However, treatment response to FLT3 inhibitors may be short-lived, and resistance may emerge. Compounds targeting STAT5 may enhance and prolong effects of FLT3 inhibitors in this subset of patients with FLT3-mutated AML. Here STAT5-inhibitor AC-4-130, FLT3 inhibitor midostaurin (PKC412), BMI-1 inhibitor PTC596, MEK-inhibitor trametinib, MCL1-inhibitor S63845, and BCL-2 inhibitor venetoclax were assessed as single agents and in combination for their ability to induce apoptosis and cell death in leukemic cells grown in the absence or presence of bone marrow stroma. Synergistic effects on cell viability were detected in both FLT3-mutated and FLT3-wild-type AML cells treated with AC-4-130 in combination with the MCL1 inhibitor S63845. AML patient samples with a strong response to AC-4-130 and S63845 combination treatment were characterized by mutated FLT3 or mutated TET2 genes. Susceptibility of AML cells to AC-4-130, PTC596, trametinib, PKC412, and venetoclax was altered in the presence of HS-5 stroma. Only the MCL1 inhibitor S63845 induced cell death with equal efficacy in the absence or presence of bone marrow stroma. The combination of the STAT5-inhibitor AC-4-130 and the MCL1 inhibitor S63845 may be an effective treatment targeting FLT3-mutated or TET2-mutated AML.

scholarly journals Cryo-ET distinguishes platelets during pre-acute myeloid leukemia from steady state hematopoiesis

2021 ◽  
Author(s):  
Yuewei Wang ◽  
Tong Huo ◽  
Yu-Jung Tseng ◽  
Lan Dang ◽  
Zhili Yu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Early Diagnosis ◽  
Myeloid Leukemia ◽  
Structural Changes ◽  
Leukemic Cells ◽  
Automatic Process ◽  
Significant Drop ◽  
Altered Expression ◽  
Cell Counts ◽  
Acute Myeloid

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes in the overall shape and depletion of organelles in AML. Notably, 23% of platelets in pre-leukemic cells exhibit abnormal, round mitochondria with unfolded cristae, accompanied by a significant drop in ATP levels and altered expression of metabolism-related gene signatures. Our study demonstrates that detectable structural changes in pre-leukemic platelets may serve as a biomarker for the early diagnosis of AML.

Antitumor Effect of Pomolic Acid in Acute Myeloid Leukemia Cells Involves Cell Death, Decreased Cell Growth and Topoisomerases Inhibition

2019 ◽  
Vol 18 (10) ◽  
pp. 1457-1468
Author(s):  
Michelle X.G. Pereira ◽  
Amanda S.O. Hammes ◽  
Flavia C. Vasconcelos ◽  
Aline R. Pozzo ◽  
Thaís H. Pereira ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Natural Compound ◽  
Dna Topoisomerases ◽  
Human Dna ◽  
Pomolic Acid ◽  
Acute Myeloid

Background: Acute myeloid leukemia (AML) represents the largest number of annual deaths from hematologic malignancy. In the United States, it was estimated that 21.380 individuals would be diagnosed with AML and 49.5% of patients would die in 2017. Therefore, the search for novel compounds capable of increasing the overall survival rate to the treatment of AML cells is urgent. Objectives: To investigate the cytotoxicity effect of the natural compound pomolic acid (PA) and to explore the mechanism of action of PA in AML cell lines with different phenotypes. Methods: Three different AML cell lines, HL60, U937 and Kasumi-1 cells with different mechanisms of resistance were used to analyze the effect of PA on the cell cycle progression, on DNA intercalation and on human DNA topoisomerases (hTopo I and IIα) in vitro studies. Theoretical experiments of the inhibition of hTopo I and IIα were done to explore the binding modes of PA. Results: PA reduced cell viability, induced cell death, increased sub-G0/G1 accumulation and activated caspases pathway in all cell lines, altered the cell cycle distribution and inhibited the catalytic activity of both human DNA topoisomerases. Conclusion: Finally, this study showed that PA has powerful antitumor activity against AML cells, suggesting that this natural compound might be a potent antineoplastic agent to improve the treatment scheme of this neoplasm.

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