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The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, suppresses survival and resistance to chemotherapy in acute myeloid leukemia cells

He, Yanli and Zhang, Jiahua and Zheng, Jin'e and Du, Wen and Liu, Wei and Li, Xiaoqing and Chen, Xiangjun and Xiao, Hong and Yang, Lin and Huang, Shiang and Jeay, Sebastien (2010) The insulin-like growth factor-I receptor kinase inhibitor, NVP-ADW742, suppresses survival and resistance to chemotherapy in acute myeloid leukemia cells. Oncology Research, 19 (1). pp. 35-43. ISSN 0965-0407

Abstract

The overexpression of Insulin-like growth factor-I receptor (IGF-IR) is strongly suggested to exert a role in malignant transformation and survival promotion in solid tumors such as breast cancer and prostate cancer, while fewer studies investigated the pathophysiological role of Insulin-like growth factor-I (IGF-I) signaling in acute myeloid leukemia (AML). In this study, we firstly found that the IGF-IR expression level positively correlated with the blast counts in de novo AML patients. Moreover, we observered that inhibitor of IGF-IR by NVP-ADW742, a novel kinase inhibitor of IGF-IR, could induce apoptosis in both HL-60 cell line and primary AML blasts, However, no significant alteration in the cell cycle status was observed in HL-60 cells. Further studies showed that NVP-ADW742 induced Akt dephosphorylation and p38 phosphorylation, decreased the expression of anti-apoptotic protein bcl-2 in HL-60 cells. Besides, we also demostrated that NVP-ADW742 could synergize with ara-C to induce apoptosis in subsets primary drug-resistant AML blasts. Therefore, IGF-IR targeting might be of therapeutic benefit for some AML patients.

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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16
URI: https://oak.novartis.com/id/eprint/2572

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