Increased expression of insulin-like growth factor I is associated with Ara-C resistance in leukemia

Shori Abe, Tadao Funato, Shinichiro Takahashi, Hisayuki Yokoyama, Joji Yamamoto, Yasuo Tomiya, Minami Yamada-Fujiwara, Kenichi Ishizawa, Junichi Kameoka, Mitsuo Kaku, Hideo Harigae, Takeshi Sasaki

Research output: Contribution to journalArticle

42 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)217-228
Number of pages12
JournalTohoku Journal of Experimental Medicine
Volume209
Issue number3
DOIs
Publication statusPublished - 2006 Jun 16

Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • Ara-C
  • Drug resistance
  • Insulin-like growth factor I

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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