Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.
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.
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.
Man-Yu
MY
Liu
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.|Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
Wei-Zhang
WZ
Wang
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.|Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
Fen-Fang
FF
Liao
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.|Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
Qing-Qing
QQ
Wu
Department of Clinical Laboratory, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, P. R. China.
Xiang-Hua
XH
Lin
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.|Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
Yong-Hen
YH
Chen
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.|Department of Biochemistry and Molecular Biology, School of Basic Courses, Guangdong Pharmaceutical University, Guangzhou, P. R. China.
Lin
L
Cheng
Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.
Xiao-Bao
XB
Jin
School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, P. R. China.|Guangdong Provincial Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou Higher Education Mega Center, Guangzhou, 510006, P. R. China.
Jia-Yong
JY
Zhu
D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D005047:Etoposide / Q000494:pharmacology* / Q000627:therapeutic use; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology* / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology*; D014410:Tumor Stem Cell Assay
D018952:Antigens, CD34; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D000068877:Imatinib Mesylate
chronic myeloid leukemia; etoposide; imatinib mesylate; leukemia stem cells