Silver nanoparticles synthesized from Aloe barbadensis leaf extract induces G0/G1 cell cycle arrest in THP-1 acute monocytic leukemia cells

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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Solasonine Suppresses the Proliferation of Acute Monocytic Leukemia Through the Activation of the AMPK/FOXO3A Axis

Frontiers in Oncology ◽

10.3389/fonc.2020.614067 ◽

2021 ◽

Vol 10 ◽

Author(s):

Hong Zhang ◽

Fang Tian ◽

Pengjun Jiang ◽

Shushu Qian ◽

Xingbin Dai ◽

...

Keyword(s):

Cell Cycle ◽

Cell Cycle Arrest ◽

Acute Monocytic Leukemia ◽

Monocytic Leukemia ◽

Antitumor Effects ◽

Cycle Arrest ◽

Compound C ◽

M Phase

Solasonine, the main active ingredient of Solanum nigrum L., has been reported to exert extensive antitumor activity. However, the antitumor effects in acute monocytic leukemia and the exact mechanisms involved are unknown. In this study, we investigated the role of solasonine on inhibiting the progression of acute monocytic leukemia. Our findings showed that solasonine inhibited the proliferation of acute monocytic leukemic cell lines (THP-1 and MV4-11) in vitro. Solasonine promoted apoptosis and induced cell cycle arrest in the G2/M phase. Analysis of RNA-seq data suggested that solasonine correlated with increased expression of genes in the AMPK/FOXO3A pathway. Inhibition of AMPK with compound C followed by treatment with solasonine showed that solasonine reduced apoptosis, caused less cell cycle arrest, and inactivated the AMPK/FOXO3A axis in THP-1 and MV4-11 cells. Solasonine also inhibited tumor growth by the activation of the AMPK/FOXO3A axis. In conclusion, solasonine inhibited the progress of acute monocytic leukemia in vitro and in vivo and triggered the apoptosis and cell cycle arrest in the G2/M phase by upregulating the AMPK/FOXO3A pathway.

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JAZ “Targeting” Compounds Induce G1 Cell Cycle Arrest Followed by Cell Death in Human Leukemia Cells

Blood ◽

10.1182/blood.v112.11.2658.2658 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2658-2658

Author(s):

Mingli Yang ◽

George Q. Yang ◽

Jinghua Jia ◽

David Ostrov ◽

W. Stratford May

Keyword(s):

Cell Cycle ◽

Cell Death ◽

Cell Cycle Arrest ◽

Cell Lines ◽

Lymphoblastic Leukemia ◽

Leukemia Cell ◽

Leukemia Cells ◽

Human Leukemia ◽

Cycle Arrest ◽

G1 Cell Cycle Arrest

Abstract JAZ (just another zinc finger protein) was previously identified in our laboratory as a unique ZFP that preferentially binds to double-stranded (ds) RNA rather than dsDNA. We found that interleukin-3 growth factor withdrawal upregulates JAZ expression in factor-dependent hematopoietic cells in association with p53 activation and induction of apoptotic cell death. We recently discovered JAZ as a novel direct, positive regulator of p53 transcriptional activity. The mechanism involves direct binding to p53’s C-terminal (negative) regulatory domain to activate “latent” p53 in response to non-genotoxic stress signals. Our preliminary data indicate that JAZ is differentially expressed in murine and human bone marrow cells and in normal and malignant hematopoietic tissues and cell lines. Thus, we have explored JAZ as a potentially novel molecular target in human leukemia by identifying small molecules that bind and activate JAZ. Using a high-throughput, “molecular docking” strategy, we have screened approximately 240,000 small molecules for their ability to interact with JAZ. Based on the Lipinski Rules for Drug Likeness (molecular characteristics favorable for absorption and permeability), we identified ~70 putative “drug-like” binding molecules with high scores and obtained ~40 of them from the NCI Developmental Therapeutics Program. We first tested their cytotoxic effect on various human leukemia cell lines including wt p53 expressing Reh pre-B lymphoblastic leukemia and Molt-3 T-cell lymphoblastic leukemia cells, and p53-deficient U937 leukemic monocyte lymphoma and KU812 and K562 chronic myelogenous leukemia cells. We have selected four “candidate” JAZ-targeting (J1-J4) compounds for further investigation because they are potent (IC50 = <1 to ~50 μM) in killing leukemia cells in association with upregulation of JAZ protein expression and p53 activation. Since we previously demonstrated that JAZ can induce G1 cell cycle arrest prior to apoptosis in NIH3T3 mouse fibrablast cells in association with upregulation of p21, dephosphorylation of Rb and repression of cyclin A, we have tested these J-compounds for their potential effect on cell cycle progression. Drug treatment followed by flow cytometry analysis was carried out in human leukemia cell lines. Results reveal that the J2, J3 and J4 but not J1 compounds induce significant G1 cell cycle arrest followed by cell death in a dose- and time-dependent manner (e.g. an increase in the G1 population by up to 35 % at 24 hr following the treatment at doses of 0.1 to 50 μM). These data indicate that the J2-J4 compounds can not only induce leukemia cell killing but also mediate growth arrest. Interestingly, J3 and J4 are FDA-approved drugs (for the treatment of non-cancer diseases), suggesting a potentially novel role for these clinically available drugs as therapy for hematologic malignancies. Therefore, while further in vitro and in vivo characterization remains to be carried out, the JAZ-“targeting” compound(s) points the way to develop a potentially novel therapeutic strategy targeting JAZ to treat human leukemia.

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