title: Inhibition of MDM2 by nilotinib contributes to cytotoxicity in both Philadelphia-positive and negative acute lymphoblastic leukemia.
abstract: Nilotinib is a selective BCR-ABL tyrosine kinase inhibitor related to imatinib that is more potent than imatinib. Nilotinib is widely used to treat chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). The present study identifies Mouse double minute 2 homolog (MDM2) as a target of nilotinib. In studying ALL cell lines, we found that the expression of MDM2 in both Philadelphia positive (Ph+) and Philadelphia negative (Ph-) ALL cells was remarkably inhibited by nilotinib, in a dose- and time-dependent manner. Further studies demonstrated that nilotinib inhibited MDM2 at the post-translational level by inducing MDM2 self-ubiquitination and degradation. Nilotinib-mediated MDM2 downregulation did not result in accumulation and activation of p53. Inhibition of MDM2 in nilotinib-treated ALL cells led to downregulation of the anti-apoptotic protein X-linked inhibitor of apoptosis protein (XIAP), a translational target of MDM2, resulting in activation of caspases. Inhibition of XIAP following nilotinib-mediated downregulation of MDM2 resulted in apoptosis of MDM2-expressing ALL; however, similar nilotinib treatment induced stronger apoptosis in Ph+/MDM2+ ALL than in Ph-/MDM2+ or Ph+/MDM2- ALL. The ALL cells that were Ph-/MDM2- were totally resistant to nilotinib. These results suggested that nilotinib can inhibit MDM2 and induce a p53-independent apoptosis pathway by downregulating XIAP; thus, nilotinib can treat not only Ph+, but also Ph- ALL patients whose cancer cells overexpress MDM2.
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Hailong
authors: H
authors: Zhang
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Lubing
authors: L
authors: Gu
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Tao
authors: T
authors: Liu
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Kuang-Yueh
authors: KY
authors: Chiang
authors: Department of Pediatrics and Aflac Cancer and Blood Disorders Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors: Muxiang
authors: M
authors: Zhou
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology* / Q000633:toxicity; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D016159:Tumor Suppressor Protein p53; D051636:X-Linked Inhibitor of Apoptosis Protein; D051736:Proto-Oncogene Proteins c-mdm2; D016044:Fusion Proteins, bcr-abl; C498826:nilotinib