title: The insulin-like growth factor-I receptor kinase inhibitor NVP-ADW742 sensitizes medulloblastoma to the effects of chemotherapy.
abstract: Medulloblastoma is the most common malignant tumor of the central nervous system in children. The insulin-like growth factor-I receptor (IGF-IR) is an important growth factor for medulloblastoma. The novel IGF-I receptor (IGF-IR) kinase inhibitor NVP-ADW742 has in vitro activity against tumors. Daoy cells were treated with NVP-ADW742 combined with temozolomide, which is commonly used in the chemotherapy of medulloblastoma. The effects on proliferation were assayed by CCK-8 assay. Cell cycle status and apoptosis were assayed by FACS analysis. The IGF-IR signaling pathway was analyzed by RT2 Profiler™ PCR arrays and Western blotting. NVP-ADW742 inhibited IGF-IR-mediated proliferation with an IC50 of 11.12 µmol/l. The PCR array data suggested that 14 genes were down-regulated at the mRNA level after NVP-ADW742 treatment. Western blot analysis suggested that NVP-ADW742 induced early suppression of Akt, P38 and GSK-3β phosphorylation, as well as a decrease in the intracellular levels of PI3K, Akt, P38, GSK-3β and Bcl-2. Combined with NVP-ADW742 (2 µmol/l), IC50 of Daoy to temozolomide was decreased from 452.12 to 256.81 µmol/l. Cell apoptosis was enhanced from 16.18±2.47% to 23.20 ± 2.80%. G phase arrest was also found in both the temozolomide alone group and the temozolomide combined with NVP-ADW742 group. NVP-ADW742 inhibited the activation of PI3K, Akt, P38 and GSK-3β caused by temozolomide. NVP-ADW742 enhanced the chemosensitivity of Daoy to temozolomide in vitro, as a potent anti-tumor agent highly selective against IGF-IR.
authors: Department of Neurosurgery, The 2nd Affiliated Hospital of Wenzhou Medical College, Wenzhou 325000, PR China.
authors: Hui
authors: H
authors: Zhou
authors: Jing
authors: J
authors: Rao
authors: Jian
authors: J
authors: Lin
authors: Bo
authors: B
authors: Yin
authors: Hansong
authors: H
authors: Sheng
authors: Fengchun
authors: F
authors: Lin
authors: Nu
authors: N
authors: Zhang
authors: Lin
authors: L
authors: Yang
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002469:Cell Separation; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D008527:Medulloblastoma / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors; D000077204:Temozolomide
chemical_list: D011743:Pyrimidines; D011758:Pyrroles; D003606:Dacarbazine; D017526:Receptor, IGF Type 1; C502355:NVP ADW742; D000077204:Temozolomide