Insulin-Like Growth Factor-Type 1 Receptor Inhibitor NVP-AEW541 Enhances Radiosensitivity of PTEN Wild-Type but Not PTEN-Deficient Human Prostate Cancer Cells

Journal Article · Thu Sep 01 00:00:00 EDT 2011 · International Journal of Radiation Oncology, Biology and Physics

DOI:https://doi.org/10.1016/j.ijrobp.2011.03.030· OSTI ID:21587688

Swinnen, Johannes V ^[1]; McBride, William H ^[2]; Haustermans, Karin M ^[3]

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1. Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven (Belgium)
2. Department of Radiation Oncology, University of California at Los Angeles, CA (United States)
3. Department of Radiation Oncology, University Hospitals Leuven Campus Gasthuisberg, Leuven (Belgium)

Purpose: During the past decade, many clinical trials with both monoclonal antibodies and small molecules that target the insulin-like growth factor-type 1 receptor (IGF-1R) have been launched. Despite the important role of IGF-1R signaling in radioresistance, studies of such agents in combination with radiotherapy are lagging behind. Therefore, the aim of this study was to investigate the effect of the small molecule IGF-1R kinase inhibitor NVP-AEW541 on the intrinsic radioresistance of prostate cancer cells. Methods and Materials: The effect of NVP-AEW541 on cell proliferation, cell viability, IGF-1R signaling, radiosensitivity, cell cycle distribution, and double strand break repair was determined in three human prostate cancer cell lines (PC3, DU145, 22Rv1). Moreover, the importance of the PTEN pathway status was explored by means of transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Results: NVP-AEW541 inhibited cell proliferation and decreased cell viability in a time-and dose-dependent manner in all three cell lines. Radiosensitization was observed in the PTEN wild-type cell lines DU145 and 22Rv1 but not in the PTEN-deficient PC3 cell line. NVP-AEW541-induced radiosensitization coincided with downregulation of phospho-Akt levels and high levels of residual double strand breaks. The importance of PTEN status in the radiosensitization effect was confirmed by transfection experiments with constitutively active Akt or inactive kinase-dead Akt. Conclusions: NVP-AEW541 enhances the effect of ionizing radiation in PTEN wild-type, but not in PTEN-deficient, prostate cancer cells. Proper patient selection based on the PTEN status of the tumor will be critical to the achievement of optimal results in clinical trials in which the combination of radiotherapy and this IGF-1R inhibitor is being explored.

• OSTI ID: 21587688
• Journal Information: International Journal of Radiation Oncology, Biology and Physics, Vol. 81, Issue 1; Other Information: DOI: 10.1016/j.ijrobp.2011.03.030; PII: S0360-3016(11)00493-7; Copyright (c) 2011 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0360-3016
• Country of Publication: United States
• Language: English

Related Subjects

62 RADIOLOGY AND NUCLEAR MEDICINE
CELL PROLIFERATION
IONIZING RADIATIONS
MONOCLONAL ANTIBODIES
NEOPLASMS
PROSTATE
RADIATION DOSES
RADIOSENSITIVITY
RADIOTHERAPY
RECEPTORS
STRAND BREAKS
ANTIBODIES
BODY
DISEASES
DNA DAMAGES
DOSES
GLANDS
MALE GENITALS
MEDICINE
MEMBRANE PROTEINS
NUCLEAR MEDICINE
ORGANIC COMPOUNDS
ORGANS
PROTEINS
RADIATIONS
RADIOLOGY
SENSITIVITY
THERAPY