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: Yanli He, Jiahua Zhang, Jine Zheng, Wen Du, Hong Xiao, Wei Liu, Xiaoqing Li, Xiangjun Chen, Lin Yang, Shiang Huang
• Journal: Oncology research (Oncol Res) Vol. 19 Issue 1 Pg. 35-43 ( 2010) ISSN: 0965-0407 [Print] United States
• PMID: 21141739 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Kinase Inhibitors
• Pyrimidines
• Pyrroles
• Cytarabine
• Receptor, IGF Type 1
• NVP ADW742

Topics

• Apoptosis (drug effects)
• Cytarabine (pharmacology)
• Drug Resistance, Neoplasm
• HL-60 Cells
• Humans
• Leukemia, Myeloid, Acute (drug therapy, mortality, pathology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Receptor, IGF Type 1 (antagonists & inhibitors, physiology)
• Signal Transduction