The Insulin-Like Growth Factor-I Receptor Kinase Inhibitor, NVP-ADW742, Sensitizes medulloblastoma to the Effects of Chemotherapy
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Zhou, Hui, Rao, Jing, Lin, Jian, Yin, Bo, Sheng, Hansong, Lin, Fengchun, 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 |