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Cell Biol Int. 2017 Jan;41(1):16-23. doi: 10.1002/cbin.10686. Epub 2016 Nov 16.

Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.

Liu MY1,2, Wang WZ2,3, Liao FF2,3, Wu QQ2,3, Lin XH4, Chen YH2,3, Cheng L2,3, Jin XB2, Zhu JY1,2.

Author information

1
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.
2
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.
3
Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
4
Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China.

Abstract

Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34+ CD38- stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34- cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34+ cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.

KEYWORDS:

chronic myeloid leukemia; etoposide; imatinib mesylate; leukemia stem cells

PMID:
27677634
DOI:
10.1002/cbin.10686
[Indexed for MEDLINE]

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