title: The insulin-like growth factor-1 receptor kinase inhibitor, NVP-ADW742, suppresses survival and resistance to chemotherapy in acute myeloid leukemia cells.
abstract: Deregulation of insulin-like growth factor-1 receptor (IGF-1R) is closely associated with malignant transformation and tumor cell survival in various cancers. We found that IGF-1R expression level in leukemia cells positively correlated with the percentage of blast in bone marrow from de novo acute myeloid leukemia (AML) patients. Moreover, we showed that NVP-ADW742, a novel small weight molecular inhibitor of IGF-IR, could induce apoptosis in both HL-60 cell line and primary AML blasts. However, no significant alteration of cell cycle was observed in HL-60 cells. Further studies revealed that NVP-ADW742 induced Akt dephosphorylation, which might subsequently induce p38 phosphorylation and decrease antiapoptotic protein Bcl-2 expression in HL-60 cells. Finally, we demonstrated that NVP-ADW742 could synergize with Ara-C to induce the kill in a subset of drug-resistant AML specimens. We suggested that IGF-lR targeting might be therapeutically beneficial for some AML patients.
authors.affiliation: Center for Stem Cell Research and Application, Institute of Hematology, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Yanli
authors.initials: Y
authors.lastname: He
authors.forename: Jiahua
authors.initials: J
authors.lastname: Zhang
authors.forename: Jine
authors.initials: J
authors.lastname: Zheng
authors.forename: Wen
authors.initials: W
authors.lastname: Du
authors.forename: Hong
authors.initials: H
authors.lastname: Xiao
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Li
authors.forename: Xiangjun
authors.initials: X
authors.lastname: Chen
authors.forename: Lin
authors.initials: L
authors.lastname: Yang
authors.forename: Shiang
authors.initials: S
authors.lastname: Huang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D003561:Cytarabine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; D003561:Cytarabine; D017526:Receptor, IGF Type 1; C502355:NVP ADW742