Antisense treatment of IGF-IR induces apoptosis and enhances chemosensitivity in central nervous system atypical teratoid/rhabdoid tumours cells

• Published in: European journal of cancer (1990) 2007-07, Vol.43 (10), p.1581-1589
• Main Authors: D’cunja, J, Shalaby, T, Rivera, P, von Büren, A, Patti, R, Heppner, F.L, Arcaro, A, Rorke-Adams, L.B, Phillips, P.C, Grotzer, M.A
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - therapeutic use; Antisense oligonucleotide; Apoptosis - drug effects; Biological and medical sciences; Brain tumours; Central Nervous System Neoplasms - drug therapy; Central Nervous System Neoplasms - pathology; Child; Child, Preschool; Cisplatin - therapeutic use; Down-Regulation; Doxorubicin - therapeutic use; Female; Hematology, Oncology and Palliative Medicine; Humans; Infant; Insulin-Like Growth Factor I - metabolism; Male; Medical sciences; Novel therapies; Oligoribonucleotides, Antisense - therapeutic use; Pharmacology. Drug treatments; Receptor, IGF Type 1 - drug effects; Receptor, IGF Type 1 - metabolism; Rhabdoid Tumor - drug therapy; Rhabdoid Tumor - pathology; Rhabdoid tumour; Teratoma - drug therapy; Teratoma - pathology; Tumors
• ISSN: 0959-8049; 1879-0852
• DOI: 10.1016/j.ejca.2007.03.003

Abstract Central nervous system (CNS) atypical teratoid/rhabdoid tumours (AT/RT) are among the paediatric malignant tumours with the worst prognosis and fatal outcome. Insulin-like growth factor I receptor (IGF-IR) protects cancer cells from apoptosis induced by a variety of anticancer drugs and radiation. In the present study, IGF-IR was expressed in 8/8 primary AT/RT as detected by immunohistochemistry. Moreover, we found IGF-I and IGF-II mRNA in BT-16 CNS AT/RT cells and IGF-II mRNA in BT-12 CNS AT/RT cells, and autophosphorylated IGF-IR in both cell lines, indicating the potential presence of an autocrine/paracrine IGF-I/II/IGF-IR loop in CNS AT/RT. IGF-IR antisense oligonucleotide treatment of human CNS AT/RT cells resulted in significant down-regulation of IGF-IR mRNA and protein expression, induction of apoptosis, and chemosensitisation to doxorubicin and cisplatin. These studies provide evidence for the influence of IGF-IR on cellular responses to chemotherapy and raise the possibility that curability of selected CNS AT/RT may be improved by pharmaceutical strategies directed towards the IGF-IR.