Studying the enhancement of programmed cell death by combined AG1024 and paclitaxel in a model of chronic myelogenous leukemia

Abstract

Aims: Chronic myelogenous leukemia is a clonal malignancy of the pluripotent hematopoietic stem cells that is characterized by the uncontrolled proliferation and expansion of myeloid progenitors. Myeloid progenitors express the fusion oncogene BCR-ABL, which has uncontrollable activity in malignant cells and prevents the cell apoptosis caused by some antineoplastic agents, such as paclitaxel. Targeting these abnormalities by blocking the tyrosine kinase enzymes of BCR-ABL is a promising approach for chronic myelogenous leukemia therapy. Main methods: Conventional Liu's staining is an auxiliary technique used in microscopy to enhance the contrast in microscopic images, aiding the observation of cell morphology. The KIT assay, flow cytometry of the sub-G1 analysis and the TUNEL assay were applied to estimate the apoptosis levels. RT-PCR and western blot methods were used to evaluate the key molecules conferring anti-cell-death properties. Key findings: The effects of the tyrosine kinase inhibitor AG1024 were evaluated with regard to the regulation of BCR-ABL expression, inhibition of cell proliferation, and enhanced paclitaxel-induced apoptosis in BCR-ABL-expressing K562 cell lines. AG1024 downregulated the expression of BCR-ABL and anti-apoptosis factors, such as Bc1-2 and Bc1-xL, which were present in K562 cells. Moreover, the combination of AG1024 with paclitaxel inhibited cell proliferation and enhanced paclitaxel-induced apoptosis within 24 h. Significance: In summary, the present study shows that the combination of AG1024 with paclitaxel inhibited model cancer cell proliferation, suggesting a new use of paditaxel-based chemotherapy for cancer control. (C) 2014 Elsevier Inc. All rights reserved.