MiR-335-3p inhibits cell proliferation, induces cell cycle arrest and apoptosis in acute myeloid leukemia by targeting EIF3E

2021 ◽  
Author(s):  
Ling Zhang ◽  
Xiaozhen Wang ◽  
Jieying Wu ◽  
Ruozhi Xiao ◽  
Jiajun Liu
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
G1 Arrest ◽  
Cycle Arrest ◽  
Promising Therapeutic Target ◽  
Reverse Transcription Quantitative Pcr ◽  
Acute Myeloid

Abstract Here, we aimed to investigate the biological roles and the regulatory mechanisms of miR-335-3p in acute myeloid leukemia (AML). We first found miR-335-3p was significantly down-regulated in blood samples from leukemia patients and cell lines using reverse transcription quantitative PCR. Through CCK-8 assay and flow cytometry, we observed that miR-335-3p overexpression significantly inhibited cell proliferation, induced cell cycle G0/G1 arrest and apoptosis in AML cell lines (THP-1 and U937). Moreover, miR-335-3p directly targets EIF3E and negatively regulated its expression. More importantly, EIF3E overexpression reversed the effects of miR-335-3p on cell proliferation, G1/S transition and apoptosis. Furthermore, miR-335-3p overexpression obviously downregulated the expression of CDK4, Cyclin D1 and Bcl-2, while upregulated the expression of p21 and Bad, which were significantly rescued by the co-transfection of pcDNA3.1-EIF3E. Collectively, our study proposes that miR-335-3p/EIF3E axis could be a promising therapeutic target to mitigate the progression of AML.

RNAi-Based Functional Genomics Screening of the Human Kinome Identifies Major Growth Regulating Kinases in Acute Myeloid Leukemia Cells

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2951-2951
Author(s):  
Raoul Tibes ◽  
Ashish Choudhary ◽  
Amanda Henrichs ◽  
Sadia Guled ◽  
Irma Monzon ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Gene Silencing ◽  
Functional Genomics ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Large Scale ◽  
Cell Cycle Checkpoint ◽  
Acute Myeloid

Abstract In order to improve treatment strategies for Acute Myeloid Leukemia (AML), we adapted a functional genomics approach using RNAi screening to identify molecular targets that are vital to the growth of AML. Herein we report the first large-scale kinome gene silencing screen in AML. A high throughput RNAi screen was developed for the efficient siRNA transfection of AML cell lines. Eight commercially available cationic lipid-based transfection reagents were tested for their ability to transfect several AML cell lines with siRNA. These extensive transfection optimization experiments identified two AML cells lines TF-1 and ML4 with up to 95–100 and 70–75% transfection efficiency respectively. Two independent replicate kinome screens were performed on both cell lines using a siRNA library targeting 572 kinase genes with 2 siRNA/gene. At 96 hours post transfection, cell proliferation was assessed and the B-score method was used to background correct and analyze the screening data. Several siRNA to specific kinases were identified that significantly inhibit cell proliferation of up to ~40–88%. Hits were defined at two thresholds: siRNA having a B-score of <−2 providing a statistically significance of p<0.05 (confidence of > 95%) and a cutoff B-score of <−1.5 providing greater than 87% confidence for each siRNA hit. Two different kinases (2 siRNA/gene/screen) were identified as major growth regulating kinases in TF1 cells with all 4 siRNA/gene having a B-score <−2. For two additional kinases, 3/4 siRNA for each gene had a Bscore <−2. Expanding the cutoff to a B-score <−1.5 three further kinases were targeted by at least 3/4 siRNA/gene. Similar analysis using the same criteria for ML4 cells identified one kinase targeted by 3/4 siRNA at a B-score <−2, seven kinases with 2/4 siRNA <−2 and two kinases with 3/4 siRNA/gene at a B-score of <−1.5. Common hits for both cell lines with at least 6/8 siRNA per gene from 4 screens performing at a B-score <−2 identified two kinases, one of them PLK1. Applying a B-score threshold of <−1.5, we identified five kinases for which at least 5/8 siRNA/gene from 4 screens met these criteria. Kinases/genes will be presented at the meeting.Confirmation of gene silencing and validation of growth response is currently underway for a subset of genes. Among the strongest hits are siRNA targeting PLK1, as well as siRNA targeting three other kinase-genes involved in regulating cell cycle progression and checkpoints and gene ontology (GO) analysis showed enrichment in cell cycle and cell cycle-checkpoint processes. Inhibitors against PLK1 and other kinase hits identified in the screen are in (pre)-clinical development and if confirmed, our experiments provide a strong rational to test these in AML. The application of RNAi based screening is useful in the identification of genes important in AML proliferation, which could serve as targets for therapeutic intervention and guide AML drug development. Furthermore, results from these types of functional genomics approaches hold promise to be rapidly translated into clinical application.

Autophagy Inhibition Enhances CDK4/6 Inhibitor-Induced Apoptosis in t(8;21) Acute Myeloid Leukemia Cells

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 50-50
Author(s):  
Kana Nakatani ◽  
Hidemasa Matsuo ◽  
Yutarou Harata ◽  
Moe Higashitani ◽  
Asami Koyama ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
G1 Phase ◽  
Therapeutic Approaches ◽  
Cycle Arrest ◽  
Induced Apoptosis ◽  
Autophagy Inhibition ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a genetically and clinically heterogeneous disease. Although t(8;21) AML patients have a more favorable prognosis than other cytogenetic subgroups, nearly 40% of t(8;21) AML patients experience relapse. Therefore, novel therapeutic approaches based on a better understanding of the biology of t(8;21) AML need to be developed. In this study, at first, we re-analyzed the sequencing data of 149 pediatric t(8;21) AML patients from St. Jude Children's Research Hospital tissue resource core facility and the JPLSG AML-05 study, and 134 adult t(8;21) AML patients from CALGB/Alliance trials and the University Hospital of Ulm. In pediatric patients, 13 CCND2 mutations were detected in 11 patients (11/149, 7.4%), and in adult patients, 14 CCND2 mutations were detected in 12 patients (12/134, 9.0%). In both cohorts, CCND2 mutations were located on the PEST domain, suggesting that the mutations stabilize the cyclin D2 protein. Next, we compared CCND2 mRNA expression between t(8;21) AML patients (n=24) and non-t(8;21) AML patients (n=163) using the TARGET AML cohort. In non-t(8;21) AML patients, CCND2 expression varied from low to high levels, whereas in t(8;21) AML patients, CCND2 expression was restricted to higher levels. Consistently, CCND2 expression was higher in t(8;21) AML cell lines (n=2: Kasumi-1 and SKNO-1), compared with non-t(8;21) AML cell lines (n=32). Kasumi-1 cells transfected with shCCND2 showed cell cycle arrest at G1 phase and impaired cell proliferation. These results suggest that the frequency of CCND2 mutations and CCND2 expression are increased in t(8;21) AML, and high CCND2 expression plays an important role in t(8;21) AML cell proliferation. Because CCND2 is not a druggable target, we examined the effect of CDK4/6 inhibitors (palbociclib and abemaciclib) on t(8;21) AML cells. Analysis of 19 AML cell lines showed that t(8;21) AML cells had lower IC50 values for CDK4/6 inhibitors than non-t(8;21) AML cells. CDK4/6 inhibitors caused cell cycle arrest at G1 phase and impaired cell proliferation in t(8;21) AML cells. To identify potential therapeutic approaches in combination with CDK4/6 inhibitors in t(8;21) AML, we performed microarray analysis and examined the effects of CDK4/6 inhibition. In addition to the pathways associated with the cell cycle (regulation of sister chromatid separation, retinoblastoma gene, and cell cycle), the MAP-ERK and PI3K-AKT-mTOR signaling pathways were downregulated by CDK4/6 inhibition. Because these pathways are involved in autophagy regulation via mTOR, we focused on examining autophagy in subsequent experiments. Assessment of the effect of CDK4/6 inhibition on autophagy in t(8;21) AML cells showed that the CDK4/6 inhibitor (abemaciclib) treatment induced LC3B-I to LC3B-II conversion in both Kasumi-1 and SKNO-1 cells. Transmission electron microscopic examination of autophagosome formation detected a large number of autophagosomes in the cytoplasm of Kasumi-1 and SKNO-1 cells treated with abemaciclib, whereas few autophagosomes were detected in control samples. These results suggest that autophagy is induced by CDK4/6 inhibition in t(8;21) AML cells. Autophagy is involved in the resistance to chemotherapy in cancer cells, therefore, we hypothesized that autophagy inhibition may be a promising therapeutic approach. Treatment of t(8;21) AML cells with the autophagy inhibitors chloroquine (CQ) or LY294002 in combination with abemaciclib significantly increased the frequency of apoptotic (Annexin V positive) cells compared with that in untreated cells, whereas CQ or LY294002 single treatment had no significant effect on apoptosis. Consistently, combinatorial inhibition of CDK4/6 and autophagy upregulated cleaved caspase 3 expression. The combinatorial effect was confirmed by silencing the autophagy-related protein ATG7 using small interfering RNA in abemaciclib-treated t(8;21) AML cells. These results suggest that autophagy inhibition enhances CDK4/6 inhibitor-induced apoptosis in t(8;21) AML cells. In conclusion, the present results indicate that inhibition of CDK4/6 and autophagy may be a novel and promising biomarker-driven therapeutic strategy for the treatment of t(8;21) AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Boswellia dalzielii-Mediated Silver Nanoparticles Inhibited Acute Myeloid Leukemia (AML) Kasumi-1 Cells by Inducing Cell Cycle Arrest

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Ismail Abiola Adebayo ◽  
Adamu Ibrahim Usman ◽  
Fatimah Bukola Shittu ◽  
Noor Zafirah Ismail ◽  
Hasni Arsad ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Silver Nanoparticles ◽  
Acute Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Myeloid Leukemia ◽  
Stem Bark ◽  
Leukemia Cells ◽  
Cycle Arrest ◽  
Acute Myeloid

Background. Acute myeloid leukemia (AML) persists to be a major health problem especially among children as effective chemotherapy to combat the disease is yet to be available. Boswellia dalzielii is a well-known herb that is traditionally used for treatment and management of many diseases including degenerative diseases. In this study, silver nanoparticles were synthesized from the phytochemicals of B. dalzielii stem bark aqueous extract. The silver nanoparticles were characterized by carrying out Fourier Transform Infrared (FTIR) spectroscopy, Energy Filtered Scanning Electron Microscopy (FESEM), X-ray diffraction, and Dynamic Light Scattering (DLS) analyses. Antioxidant capacity of the nanoparticles was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay, and the antiproliferative effect of the nanoparticles on Kasumi-1 leukemia cells was investigated using PrestoBlue assay. Flow cytometry analysis was performed to observe the effect of the nanoparticles on the leukemia cell cycle progression. Results. Our findings revealed that the synthesized silver nanoparticles were formed from electrons of the plant phytochemicals which include aromatic compounds, ethers, and alkynes. FESEM analysis revealed that the sizes of the nanoparticles range from 12 nm to 101 nm; however, DLS analysis estimated a larger average size of the nanoparticles (108.3 nm) because it measured the hydrodynamic radii of the nanoparticles. The zeta potential of the nanoparticles was −16 nm, and the XRD pattern of the nanoparticles has distinct peaks at 38.02°, 42.94°, 64.45°, 77.20°, and 81.47°, which is typical of face-centered cubic (fcc) structure of silver. The Trolox Equivalence Antioxidant Capacity (TEAC) of the nanoparticles was estimated to be 300.91 μM Trolox/mg silver nanoparticles. The nanoparticles inhibited Kasumi-1 cell proliferation. The half minimal inhibitory concentrations (IC50s) that inhibited Kasumi-1 cell proliferation are 49.5 μg/ml and 13.25 μg/ml at 48 and 72 hours, respectively. The nanoparticles induced cell cycle arrest in the Kasumi-1 cells at S (5% increase) and G2/M (3% increase) phases. Conclusion. The nanoparticles synthesized from the stem bark extract of B. dalzielii inhibit the growth of Kasumi-1 leukemia cells by activating cell cycle arrest; thus, they are potential antileukemic agents.

scholarly journals MicroRNA-582–3p negatively regulates cell proliferation and cell cycle progression in acute myeloid leukemia by targeting cyclin B2

2019 ◽  
Vol 24 (1) ◽  
Author(s):  
Haixia Li ◽  
Xuefei Tian ◽  
Paoqiu Wang ◽  
Mao Huang ◽  
Ronghua Xu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Cell Cycle Progression ◽  
Target Gene ◽  
Cycle Progression ◽  
Blood Samples ◽  
Acute Myeloid

Abstract Background MicroRNAs (miRNAs) function as post-transcriptional gene expression regulators. Some miRNAs, including the recently discovered miR-582–3p, have been implicated in leukemogenesis. This study aimed to reveal the biological function of miR-582–3p in acute myeloid leukemia (AML), which is one of the most frequently diagnosed hematological malignancies. Methods The expression of miR-582–3p was determined using quantitative real-time PCR in blood samples from leukemia patients and in cell lines. Cell proliferation and cell cycle distribution were analyzed using the CCK-8, colony formation and flow cytometry assays. The target gene of miR-582–3p was verified using a dual-luciferase reporter assay. The G2/M phase arrest-related molecule contents were measured using western blotting analysis. Results We found miR-582–3p was significantly downregulated in the blood samples from leukemia patients and in the cell lines. MiR-582–3p overexpression significantly impaired cell proliferation and induced G2/M cell cycle arrest in THP-1 cells. Furthermore, cyclin B2 (CCNB2) was confirmed as a target gene of miR-582–3p and found to be negatively regulated by miR-582–3p overexpression. More importantly, CCNB2 knockdown showed suppressive effects on cell proliferation and cell cycle progression similar to those caused by miR-582–3p overexpression. The inhibitory effects of miR-582–3p overexpression on cell proliferation and cell cycle progression were abrogated by CCNB2 transfection. Conclusion These findings indicate new functions and mechanisms for miR-582–3p in AML development. Further study could clarify if miR-582–3p and CCNB2 are potential therapeutic targets for the treatment of AML.

scholarly journals Adjuvant Epigenetic Therapy of Decitabine and Suberoylanilide Hydroxamic Acid Exerts Anti-Neoplastic Effects in Acute Myeloid Leukemia Cells

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1480 ◽  
Author(s):  
Sonia Abou Najem ◽  
Ghada Khawaja ◽  
Mohammad Hassan Hodroj ◽  
Patil Babikian ◽  
Sandra Rizk
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Hydroxamic Acid ◽  
Epigenetic Therapy ◽  
Suberoylanilide Hydroxamic Acid ◽  
Sequential Combination ◽  
Acute Myeloid

Atypical epigenetic processes including histone acetylation and DNA methylation have been identified as a fundamental theme in hematologic malignancies. Such mechanisms modify gene expression and prompt, in part at least, the initiation and progression of several malignancies including acute myeloid leukemia. In the current study we determined the effects of treating KG-1 and U937 acute myeloid leukemia (AML) cells, in vitro, with the HDAC inhibitor, suberoylanilide hydroxamic acid (SAHA), or with a DNMT inhibitor, decitabine (DAC), or their combination, on cell proliferation, cell cycle progression, apoptosis, and expression of apoptosis-related proteins. Each of SAHA and DAC attenuated cell proliferation and induced cell cycle arrest and apoptotic cell death of KG-1 and U937 cell lines. Besides, their sequential combination improved the obtained anti-neoplastic effect: significant augmentation of growth inhibition and apoptosis induction as compared to cells treated with either drug alone. This effect was featured by the upregulated expression of Bax, cytochrome c1, p21, and cleaved caspases 8, 9, and 3, signifying the activation of both the intrinsic and extrinsic pathways of apoptosis. The sequential combination of SAHA and DAC causes a profound antitumorigenic effect in AML cell lines by inducing the expression of tumor suppressor genes.

scholarly journals Inhibition of c-Myc By Apto-253 As an Innovative Therapeutic Approach to Induce Cell Cycle Arrest and Apoptosis in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1716-1716 ◽  
Author(s):  
Hongying Zhang ◽  
Andrea Local ◽  
Khalid Benbatoul ◽  
Peter Folger ◽  
Susan Sheng ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Transcription Factor ◽  
Cell Cycle Arrest ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Time Dependent ◽  
Cycle Arrest ◽  
Dose Dependent ◽  
Acute Myeloid

Abstract The c-Myc multifunctional transcription factor protein, a product on the c-myc proto-oncogene, contributes to the pathogenesis of many types of human cancers through mechanisms of proliferation, apoptosis, cell cycle progression and cellular senescence. c-Myc is frequently overexpressed in acute myeloid leukemia, yet strategies to effectively modulate c-Myc function do not exist. We evaluated inhibition of c-myc gene expression by APTO-253, a small molecule anticancer agent that is being developed clinically for the treatment of acute myelogenous (myeloid) leukemia (AML) and high risk myelodysplastic syndromes (MDS). We first confirmed that c-Myc mRNA level were significantly higher in AML cell lines as compared to peripheral blood mononuclear cells (PBMCs) isolated from healthy human donors. However, the c-Myc expression in AML cells was inhibited by APTO-253 in dose-dependent and time-dependent manners at both the mRNA and protein levels. Likewise, APTO-253 was found to induce AML cell apoptosis in dose-dependent and time-dependent manners as demonstrated by positive Annexin-V staining and increases in cleaved poly (ADP-ribose) polymerase (c-PARP). APTO-253 induced AML cells arrest at G1/G0 phase of cell cycle by increasing p21 expression and decreasing expression of cyclin D3 and cyclin-dependent kinases 4/6 (CDK4/6). For the p53 positive cell lines MV4-11 and EOL-1, p53 was also increased by APTO-253 at early time points (less than 6-hour treatment), suggesting that p53-dependent cell cycle arrest and apoptosis is mechanistically operative as a consequence of treatment with APTO-253. Importantly, we demonstrated that APTO-253 selectively targeted tumor cells but not normal healthy cells, with MV4-11 AML cells and normal PBMCs having IC50s of 0.25±0.03µM and more than 100µM, respectively. Our previous studies (56th ASH abstract #4813) showed that APTO-253 induces the Krüppel-like Factor 4 (KLF4) transcription factor and was effective and well tolerated as a single agent in multiple AML xenograft models without causing bone marrow suppression. Taken together, our results suggested that APTO-253 may serve as an effective and safe agent for AML chemotherapy, and that APTO-253 mechanistically inhibits c-Myc expression in AML cells and subsequently induces cell cycle arrest and apoptosis. Disclosures No relevant conflicts of interest to declare.

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.

Octadecyloxyethyl Adefovir Exhibits Potent in vitro and in vivo Cytotoxic Activity and Has Synergistic Effects with Ara-C in Acute Myeloid Leukemia

Chemotherapy ◽  
2018 ◽  
Vol 63 (4) ◽  
pp. 225-237 ◽  
Author(s):  
Haytham Khoury ◽  
Ruijuan He ◽  
Aaron Schimmer ◽  
James R. Beadle ◽  
Karl Y. Hostetler ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Dna Damage ◽  
Acute Myeloid Leukemia ◽  
Cell Cycle Arrest ◽  
Clinical Benefit ◽  
Myeloid Leukemia ◽  
Mouse Bone Marrow ◽  
Medical Needs ◽  
Cycle Arrest ◽  
Acute Myeloid

Acute myeloid leukemia (AML) continues to be a deadly disease, with only 50–70% of patients achieving complete remission and less than 30% of adults having sustained long-term remissions. In order to address these unmet medical needs, we carried out a high-throughput screen of an in-house library of on- and off-patent drugs with the OCI/AML-2 cell line. Through this screen, we discovered adefovir dipi­voxil (adefovir-DP) as being active against human AML. In addition to adefovir-DP, there are second-generation formulations of adefovir, including octadecyloxyethyl adefovir (ODE-adefovir) and hexadecyloxypropyl adefovir (HDP-adefovir), which were designed to overcome the pharmacokinetic problems of the parent compound adefovir. Given the known clinical benefit of nucleoside analogs for the treatment of AML, we undertook studies to evaluate the potential benefit of adefovir-based molecules. In AML cell lines and patient samples, adefovir-DP and ODE-adefovir were highly potent, whereas HDP-adefovir was significantly less active. Interestingly, ODE-adefovir was remarkably less toxic than adefovir-DP towards normal hematopoietic cells. In addition, ODE-adefovir at a dose of 15 mg/kg/day showed potent activity against human AML in a NOD/SCID mouse model, with a reduction of human leukemia in mouse bone marrow of > 40% in all mice tested within 20 days of treatment. Based on its chemical structure, we hypothesized that the cytotoxicity of ODE-adefovir toward AML was through cell cycle arrest and DNA damage. Indeed, ODE-adefovir treatment induced cell cycle arrest in the S phase and increased levels of pH2Ax, indicating the induction of DNA damage. Furthermore, there was an increase in phospho-p53, transactivation of proapoptotic genes and activation of the intrinsic apoptotic pathway. Subsequent investigation unveiled strong synergism between ODE-adefovir and ara-C, making their coadministration of potential clinical benefit. Expression of MRP4, a nucleoside transporter, appeared to influence the response of AML cells to ODE-adefovir, as its inhibition potentiated ODE-adefovir killing. Taken together, our findings indicate that clinical development of ODE-adefovir or related compounds for the treatment of AML is warranted.

scholarly journals Axolotl Ambystoma mexicanum extract induces cell cycle arrest and differentiation in human acute myeloid leukemia HL-60 cells

Tumor Biology ◽  
2020 ◽  
Vol 42 (9) ◽  
pp. 101042832095473
Author(s):  
Sherif Suleiman ◽  
Riccardo Di Fiore ◽  
Analisse Cassar ◽  
Melissa Marie Formosa ◽  
Pierre Schembri-Wismayer ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Crude Extract ◽  
Myeloid Leukemia ◽  
Ambystoma Mexicanum ◽  
Cycle Arrest ◽  
Human Acute Myeloid Leukemia ◽  
Acute Myeloid

Acute myeloid leukemia is the most common form of acute leukemia in adults, constituting about 80% of cases. Although remarkable progress has been made in the therapeutic scenario for patients with acute myeloid leukemia, research and development of new and effective anticancer agents to improve patient outcome and minimize toxicity is needed. In this study, the antitumor activity of axolotl (AXO) Ambystoma mexicanum crude extract was assessed in vitro on the human acute myeloid leukemia HL-60 cell line. The anticancer activity was evaluated in terms of ability to influence proliferative activity, cell viability, cell cycle arrest, and differentiation. Moreover, gene expression analysis was performed to evaluate the genes involved in the regulation of these processes. The AXO crude extract exhibited antiproliferative but not cytotoxic activities on HL-60 cells, with cell cycle arrest in the G0/G1 phase. Furthermore, the AXO-treated HL-60 cells showed an increase in both the percentage of nitroblue tetrazolium positive cells and the expression of CD11b, whereas the proportion of CD14-positive cells did not change, suggesting that extract is able to induce differentiation toward the granulocytic lineage. Finally, the treatment with AXO extract caused upregulation of CEBPA, CEBPB, CEBPE, SPI1, CDKN1A, and CDKN2C, and downregulation of c-MYC. Our data clearly show the potential anticancer activity of Ambystoma mexicanum on HL-60 cells and suggest that it could help develop promising therapeutic agents for the treatment of acute myeloid leukemia.

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