Increased Expression of Insulin-Like Growth Factor I is Associated with Ara-C Resistance in Leukemia

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  • Abe Shori
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Funato Tadao
    Department of Laboratory Science, School of Health Sciences, Faculty of Medicines, Kyoto University
  • Takahashi Shinichiro
    Department of Infection Control and Laboratory Diagnostics, Tohoku University School of Medicine
  • Yokoyama Hisayuki
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Yamamoto Joji
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Tomiya Yasuo
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Yamada-Fujiwara Minami
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Ishizawa Kenichi
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Kameoka Junichi
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Kaku Mitsuo
    Department of Infection Control and Laboratory Diagnostics, Tohoku University School of Medicine
  • Harigae Hideo
    Department of Rheumatology and Hematology, Tohoku University School of Medicine
  • Sasaki Takeshi
    Department of Rheumatology and Hematology, Tohoku University School of Medicine

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Abstract

Resistance to cytosine arabinoside (Ara-C) is a major problem in the treatment of patients with acute myeloid leukemia (AML). In order to investigate the mechanisms involved in Ara-C resistance, the gene expression profile of Ara-C-resistant K562 human myeloid leukemia cells (K562/AC cells) was compared to that of Ara-C-sensitive K562 cells (K562 cells) by using a cDNA microarray platform. Correspondence analysis demonstrated that insulin-like growth factor I (IGF-I) gene was upregulated in K562/AC cells. The biological significance of IGF-I overexpression was further examined in vitro. When K562 cells were incubated with IGF-I ligand, they were protected from apoptosis induced by Ara-C. In contrast, a significant inhibition of growth and increase of apoptosis of K562/AC cells were induced by IGF-I receptor neutralizing antibody, or suramin, a nonspecific growth factor antagonist. Moreover, from the analysis of 27 AML patients, we have shown that IGF-I expression levels are higher in patients at refractory stage, after Ara-C combined chemotherapy, than those in patients at diagnosis. These results suggest that the inhibition of IGF-I and its downstream pathway is a valuable therapeutic approach to overcome Ara-C resistance in AML.

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