Increased expression of insulin-like growth factor i is associated with Ara-C resistance in leukemia.
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.
Abe
Shori
S
Department of Rheumatology and Hematology, Tohoku University School of Medicine, Sendai, Japan.
Funato
Tadao
T
Takahashi
Shinichiro
S
Yokoyama
Hisayuki
H
Yamamoto
Joji
J
Tomiya
Yasuo
Y
Yamada-Fujiwara
Minami
M
Ishizawa
Kenichi
K
Kameoka
Junichi
J
Kaku
Mitsuo
M
Harigae
Hideo
H
Sasaki
Takeshi
T
D000208:Acute Disease; D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D003561:Cytarabine / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D051058:Oncogene Protein v-akt / Q000378:metabolism; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D013498:Suramin / Q000494:pharmacology; D015854:Up-Regulation
D003561:Cytarabine; D013498:Suramin; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; D051058:Oncogene Protein v-akt