Homoharringtonine suppresses imatinib resistance via the Bcl-6/p53 pathway in chronic myeloid leukemia cell lines.

Qian Wang,Yihan Ding,Zhaoye Qian,Yufeng Li,Jingjing Ma,Wei Ding,Jingxian Shao

doi:10.18632/oncotarget.16731

Abstract

BackgroundThe anti-leukemic mechanism of homoharringtonine (HHT) differs from that of IM, and HHT is one of the most useful agents for use in patients with IM resistance or intolerance. The Bcl-6/p53 pathway has been shown to regulate the sensitivity of tumor cells to antitumor drugs. We tested whether HHT blocked the Bcl-6/p53 pathway in order to promote the apoptosis of IM-resistant cells in vitro and in vivo.ResultsPh+ acute lymphoblastic leukemia (ALL) cells and IM-resistant chronic myeloid leukemia (CML) cells showed high expression of Bcl-6 protein. Bcl-6 mediated the upregulation of p53, and and Bcl-6 induced growth inhibition of IM-resistant cells as well as its apoptosis by targeting p53. In addition, Bcl-6 was downregulated moderately after HHT treatment in different cells. The Bcl-6 expression was significantly increased in patients with CML when compared with healthy subjects. Furthermore, the expression of Bcl-6 was higher in patients with CML-blastic phase (CML-BP) than in those with CML-chronic phase (CML-CP).MethodsThe inhibitory effect of drugs on cell growth was detected by Cell Counting Kit-8 (CCK-8), The apoptosis rate and the cell cycle were investigated by flow cytometry. The expression of Bcl-6, p53, Bcl-2, caspase9, and caspase3 proteins was assayed by western blot, Real- Time PCR (qPCR) detect Bcl-6 and p53 mRNA.ConclusionsHHT can suppress the growth and induce apoptosis of IM-resistant cells, the mechanism of which is associated with blocking of the Bcl-6/p53 pathway. Our results could offer a theoretical explanation for HHT use in patients with IM resistance or intolerance.

Highlights

Chronic myeloid leukemia (CML) arises from pluripotent hemopoietic stem cells with a reciprocal translocation between chromosomes 9 and 22 [1]
The inhibitory effect of drugs on cell growth was detected by Cell Counting Kit-8 (CCK-8), The apoptosis rate and the cell cycle were investigated by flow cytometry
HHT can suppress the growth and induce apoptosis of IM-resistant cells, the mechanism of which is associated with blocking of the Bcl-6/p53 pathway

Summary

Introduction

Chronic myeloid leukemia (CML) arises from pluripotent hemopoietic stem cells with a reciprocal translocation between chromosomes 9 and 22 [1]. The chromosomal abnormality persistently activates tyrosine kinase, resulting in the activation of a downstream signaling pathway that inhibits cell apoptosis [2,3,4]. The international randomized study (IRIS) reported a complete hematologic remission rate of 97% [6], complete cytogenetic response rate of 63% [7], and major cytogenetic response rate of 87% [8] in newly diagnosed CML-chronic phase (CML-CP) patients after 12 months of IM treatment. IM is highly effective for treating CML, it does have limitations These include an inability to eradicate leukemia stem cells (LICs) and the occurrence of primary or secondary drug resistance [10,11,12]. The drug resistance rate was 75% CML-AP and 95% in CML-BP patients [14]. We tested whether HHT blocked the Bcl-6/p53 pathway in order to promote the apoptosis of IM-resistant cells in vitro and in vivo

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Results

Conclusion