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Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro
Author(s) -
Liu ManYu,
Wang WeiZhang,
Liao FenFang,
Wu QingQing,
Lin XiangHua,
Chen YongHen,
Cheng Lin,
Jin XiaoBao,
Zhu JiaYong
Publication year - 2017
Publication title -
cell biology international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.932
H-Index - 77
eISSN - 1095-8355
pISSN - 1065-6995
DOI - 10.1002/cbin.10686
Subject(s) - imatinib mesylate , etoposide , myeloid leukemia , imatinib , pharmacology , in vitro , cancer research , chemistry , medicine , chemotherapy , biochemistry
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.