TY - JOUR
T1 - Increased expression of insulin-like growth factor I is associated with Ara-C resistance in leukemia
AU - Abe, Shori
AU - Funato, Tadao
AU - Takahashi, Shinichiro
AU - Yokoyama, Hisayuki
AU - Yamamoto, Joji
AU - Tomiya, Yasuo
AU - Yamada-Fujiwara, Minami
AU - Ishizawa, Kenichi
AU - Kameoka, Junichi
AU - Kaku, Mitsuo
AU - Harigae, Hideo
AU - Sasaki, Takeshi
PY - 2006/6/16
Y1 - 2006/6/16
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Apoptosis
KW - Ara-C
KW - Drug resistance
KW - Insulin-like growth factor I
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U2 - 10.1620/tjem.209.217
DO - 10.1620/tjem.209.217
M3 - Article
C2 - 16778368
AN - SCOPUS:33745200955
SN - 0040-8727
VL - 209
SP - 217
EP - 228
JO - Tohoku Journal of Experimental Medicine
JF - Tohoku Journal of Experimental Medicine
IS - 3
ER -