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The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes medulloblastoma to the Effects of Chemotherapy

Zhou, Hui and Rao, Jing and Lin, Jian and Yin, Bo and Sheng, Hansong and Lin, Fengchun and Zhang, Nu and Yang, Lin (2011) The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes medulloblastoma to the Effects of Chemotherapy. Oncology Reports, 25 (6). pp. 1565-1571. ISSN 1021-335X

Abstract

Medulloblastoma is the most common malignant tumor of central nervous system in children. The insulin-like growth factor-I receptor (IGF-IR) is an important growth factor for medulloblastoma in both endocrine and autocrine contexts. The purpose of this study was to determine whether the novel IGF-I receptor (IGF-IR) kinase inhibitor, NVP-ADW742, sensitizes medulloblastoma cell line to temozolomide (TMZ), which is commonly used in the treatment of medulloblastoma.
Experimental Design: Daoy cells were treaed with NVP- ADW742 combined with temozolomide. The effects on proliferation were assayed by CCK-8 assay. The effects on cell cycle status were assayed by FACS analysis. The effects on apoptosis were assayed by Annexin V-FITC FACS analysis. The effects on IGF-IR signaling pathway were assayed by quality PCR array and western blot.
Results: IGF-IR-mediated proliferation was inhibited by NVP-ADW742 with an IC50 of 11.12µmol/L. NVP-ADW742 did not induce discernable alternation of cell cycle in Daoy cells, but NVP-ADW742 could induce the apoptosis of Daoy cells in a dose dependent manner. Quality PCR array suggested that 14 genes were down regulated in the mRNA level after NVP-ADW742 treatment, including PI3K, Akt, P38, GSK-3β and so on. Western blot suggested that NVP-ADW742 induced early suppression of Akt, P38 andGSK-3β phosphorylation, as well as decrease in intracellular levels of PI3K, Akt, P38, GSK-3β and Bcl-2. IC50 of Daoy to temozolomide was decreased from 452.12µmol/L to 256.81µmol/L combined with NVP-ADW742 (2µmol/L). NVP-ADW742 enhanced cell apoptosis from 16.18%±2.47% to 23.20%±2.80%. G phase arrested was also found in both the group temozolomide alone and the group temozolomide combined with NVP-ADW742. Temozolomide might activate the phosphorylation of Akt, P38 and GSK-3β, and the activation of PI3K, Akt, P38 and GSK-3β were inhibited by NVP-ADW742.
Conclusions: our study supported the concept that IGF-IR signaling played an important role in proliferation and apoptosis of medulloblastoma. In addition, we provide the vitro evidence that NVP-ADW742 enhanced the chemosensitivity of Daoy to temozolomide, as a potent anti-tumor agent by highly selective against IGF-IR.

Item Type: Article
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Additional Information: author cannot archive pre-print (ie pre-refereeing
Keywords: Medulloblastoma; The insulin-like growth factor-I receptor (IGF-IR); NVP- ADW742; temozolomide
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4166

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