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.

G1 Cell-Cycle Arrest and Apoptosis by Histone Deacetylase Inhibition in MLL-AF9 Acute Myeloid Leukemia Cells Is MLL-AF9 Independent.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4410-4410
Author(s):  
Roberto Tonelli ◽  
Roberta Sartini ◽  
Raffaele Fronza ◽  
Francesca Freccero ◽  
Monica Franzoni ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Acute Myeloid Leukemia ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Myeloid Leukemia ◽  
Combined Treatment ◽  
Histone Deacetylase Inhibition ◽  
Cycle Arrest ◽  
G1 Cell Cycle Arrest ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) with MLL rearrangements (MLLmut), found mainly in M5 or M4 FAB subtypes, is frequent in infants and secondary leukemias. The most common MLL translocation gives rise to MLL-AF9. MLL protein interacts with histone deacetylases (HDACs) -1 and -2 through the MLL repression domain. We report the effects of HDAC inhibition by valproic acid (VPA) in MLL-AF9 AML-M5 cells (THP-1, MM6 and MOLM-13) and MLLmut AML-M5 blasts. VPA led to histone hyper-acetylation, strong cell-growth inhibition, G1 cell-cycle arrest and apoptosis. Combined treatment with all-trans-retinoic-acid (ATRA) did not substantially improve these effects. VPA increased MLL-AF9 transcription, indicating that VPA overcomes the cell-growth promoting activity and resistance to apoptosis conferred by MLL-AF9 in AML-M5 cells, even with increased MLL-AF9. A small number of genes were significantly affected by VPA in p53-absent THP-1 cells (GeneChip analysis), and the majority of these were up-regulated. VPA potently induced p21 and cyclin G2 (CG2) expression. p21 and CG2 targeted inhibition demonstrated that p21 acts as a key regulator in the VPA-inducted G1 cell-cycle arrest, while induction of CG2 has no effect. These data suggest that these poor prognosis patients may benefit from HDAC inhibitor therapy.

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.

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