title: Enhancement of imatinib-induced apoptosis of BCR/ABL-expressing cells by nutlin-3 through synergistic activation of the mitochondrial apoptotic pathway.
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.
authors.affiliation: Department of Hematology, Tokyo Medical and Dental University, Bunkyoku, Tokyo, 113-8519, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kurosu
authors.forename: Nan
authors.initials: N
authors.lastname: Wu
authors.forename: Gaku
authors.initials: G
authors.lastname: Oshikawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Osamu
authors.initials: O
authors.lastname: Miura
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001549:Benzamides; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D007093:Imidazoles / Q000494:pharmacology*; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism; D020014:K562 Cells / Q000187:drug effects*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D001549:Benzamides; D007093:Imidazoles; D007377:Interleukin-3; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D051028:bcl-2-Associated X Protein; C482205:nutlin 3; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl