RRC ID 38228
Author Kurosu T, Wu N, Oshikawa G, Kagechika H, Miura O.
Title Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway.
Journal Apoptosis
Abstract The BCR/ABL tyrosine kinase inhibitor imatinib is highly effective for treatment of chronic myeloid leukemia (CML) and Philadelphia-chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). However, relapses with emerging imatinib-resistance mutations in the BCR/ABL kinase domain pose a significant problem. Here, we demonstrate that nutlin-3, an inhibitor of Mdm2, inhibits proliferation and induces apoptosis more effectively in BCR/ABL-driven Ton.B210 cells than in those driven by IL-3. Moreover, nutlin-3 drastically enhanced imatinib-induced apoptosis in a p53-dependent manner in various BCR/ABL-expressing cells, which included primary leukemic cells from patients with CML blast crisis or Ph+ ALL and cells expressing the imatinib-resistant E255K BCR/ABL mutant. Nutlin-3 and imatinib synergistically induced Bax activation, mitochondrial membrane depolarization, and caspase-3 cleavage leading to caspase-dependent apoptosis, which was inhibited by overexpression of Bcl-XL. Imatinib did not significantly affect the nutlin-3-induced expression of p53 but abrogated that of p21. Furthermore, activation of Bax as well as caspase-3 induced by combined treatment with imatinib and nutlin-3 was observed preferentially in cells expressing p21 at reduced levels. The present study indicates that combined treatment with nutlin-3 and imatinib activates p53 without inducing p21 and synergistically activates Bax-mediated intrinsic mitochondrial pathway to induce apoptosis in BCR/ABL-expressing cells.
Volume 15(5)
Pages 608-20
Published 2010-5-1
DOI 10.1007/s10495-010-0457-0
PMID 20094798
MeSH Animals Apoptosis* / drug effects Apoptosis* / physiology Benzamides Cell Proliferation Cell Survival Drug Resistance, Neoplasm / drug effects Drug Resistance, Neoplasm / genetics Fusion Proteins, bcr-abl / genetics Fusion Proteins, bcr-abl / metabolism* Humans Imatinib Mesylate Imidazoles / pharmacology* Interleukin-3 / genetics Interleukin-3 / metabolism K562 Cells / drug effects* Membrane Potential, Mitochondrial / drug effects Mitochondria* / drug effects Mitochondria* / metabolism Piperazines / pharmacology* Protein Kinase Inhibitors / pharmacology* Pyrimidines / pharmacology* bcl-2-Associated X Protein / metabolism
IF 4.021
Times Cited 29
Human and Animal Cells