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Effects of Glycyrrhetic Acid on Human Chronic Myelogenous Leukemia Cells.

ABSTRACT: Objectives:Chronic myelogenous leukemia (CML) is a type of blood cancer that is initially treated with imatinib (first Abl kinase inhibitor). However, some patients with CML develop imatinib resistance. Several new generation drugs have been developed, but do not overcome this problem. Glycyrrhetic acid (GA) is a plant-derived pentacyclic triterpenoid that exhibits multiple pharmacological properties for the treatment of cancers. The current study aimed to investigate the effects of GA on the K562 cell line (Bcr-Abl positive leukemia). Materials and Methods:The MTT cell proliferation assay was employed to evaluate the cytotoxic effect of GA compared with imatinib (positive control) against leukemia and normal blood cells. For detection of cell death, an apoptotic/necrotic/healthy assay was performed against the K562 cell line. To investigate the kinase inhibitory activity of GA, the Abl1 kinase profiling assay and a molecular docking study were performed. Results:GA showed Abl kinase inhibitory activity with an IC50 value of 29.2 ?M and induced apoptosis in the K562 cell line after 6 h of treatment. Conclusion:The current findings indicate that this class of plant extract could be a potential candidate for treatment of CML.

SUBMITTER: Ciftci H

PROVIDER: S-EPMC7227864 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Effects of Glycyrrhetic Acid on Human Chronic Myelogenous Leukemia Cells.

Çiftçi Halilibrahim H

Turkish journal of pharmaceutical sciences 20200219 1

<h4>Objectives</h4>Chronic myelogenous leukemia (CML) is a type of blood cancer that is initially treated with imatinib (first Abl kinase inhibitor). However, some patients with CML develop imatinib resistance. Several new generation drugs have been developed, but do not overcome this problem. Glycyrrhetic acid (GA) is a plant-derived pentacyclic triterpenoid that exhibits multiple pharmacological properties for the treatment of cancers. The current study aimed to investigate the effects of GA o ...[more]

PMID: 32454760

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Project description:We show the molecular and functional characterization of a novel population of lineage-negative CD34-negative (Lin- CD34-) hematopoietic stem cells (HSCs) from chronic myelogenous leukemia (CML) patients at diagnosis. Molecular caryotyping and quantitative analysis of BCR/ABL transcript demonstrated that about one third of CD34- was leukemic. CML CD34- cells showed kinetic quiescence and limited clonogenic capacity. However, stroma-dependent cultures and cytokines induced CD34 expression on some HSCs, cell cycling, acquisition of clonogenic activity and increased expression of BCR/ABL transcript. CML CD34- cells showed an engraftment rate in immunodeficient mice similar to that of CD34+ cells. Gene expression profiling revealed the down-regulation of cell cycle arrest genes together with genes involved in antigen presentation and processing, while the expression of angiogenic factors was strongly up-regulated when compared to normal counterparts. Flow cytometry analysis confirmed the significant down-regulation of HLA class I and II molecules in CML CD34-cells. Increasing doses of imatinib mesilate (IM) did not affect fusion transcript levels, BCR-ABL kinase activity and the clonogenic efficiency of CML CD34- cells as compared to leukemic CD34+cells. Thus, we identified in CML a novel CD34- leukemic stem cell subset with peculiar molecular and functional characteristics which may be a potential target for CML therapeutics. Leukemic cells were obtained from 12 chronic phase Ph+ CML patients at diagnosis and before treatment. Normal samples were leukapheresis products from 12 healthy stem cell donors receiving recombinant human granulocyte colony-stimulating factor (G-CSF; Lenograstim, Sanofi-Aventis, Milan, Italy). The protocol was approved by the ethical committee of the University Hospital and each patient/donor gave written informed consent. Hemopoietic stem/progenitor cell purification and phenotypic analyses were performed as previously described (Lemoli et al, Br J Haematol, 2003; Lemoli RM et al., Blood, 1997). Aliquots of sorted Lin-CD34-, Lin-CD34+ and Lin+CD34+ were reanalyzed by FacScan (Becton Dickinson, Franklin Lakes, NJ) to assess their purities. Total cellular RNA was extracted from 0.5x105 cells of each sample using RNeasy Micro kit (Qiagen, Valencia, CA) following the protocol supplied by the manufacturer. Disposable RNA chips (Agilent RNA 6000 Nano LabChip kit, Agilent Technologies, Waldbrunn, Germany) were used to determine the concentration and purity/integrity of RNA samples using Agilent 2100 Bioanalyzer. RNAs originating from 12 normal donors or from 12 CML patients were pooled in order to obtain at least 2 mg per sample. One-cycle target labeling assays, as well as the Affymetrix Human HG-U95Av2 GeneChip arrays hybridization, staining, and scanning, were performed, using Affymetrix standard protocols (Affymetrix, Santa Clara,CA).

Dataset Information

Effects of Glycyrrhetic Acid on Human Chronic Myelogenous Leukemia Cells.

Publications

Effects of Glycyrrhetic Acid on Human Chronic Myelogenous Leukemia Cells.

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