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Regulation of VEGF-expression by patupilone and ionizing radiation in lung adenocarcinoma cells


Rohrer Bley, C; Orlowski, K; Furmanova, P; McSheehy, P M; Pruschy, M (2011). Regulation of VEGF-expression by patupilone and ionizing radiation in lung adenocarcinoma cells. Lung Cancer, 73(3):294-301.

Abstract

The use of microtubule stabilizing agents (MSA) is a promising strategy for anti-cancer therapy alone and as part of combined treatment modalities with ionizing radiation. However MSA-provoked molecular and cellular processes including the regulation of intercellular, paracrine signaling pathways are far from clear. Here we investigated the interference of the novel, clinically relevant MSA patupilone (epothilone B) with the tumor-cell derived vascular endothelial growth factor (VEGF), which is most relevant for tumor angiogenesis. Low-dose, sub-nanomolar concentrations of patupilone specifically reduced hypoxia-driven stabilization of the transcription factor HIF-1α in the patupilone-sensitive lung adenocarcinoma cell line A549, but not in the mutant derivative cell line A549.EpoB40. Patupilone further reduced hypoxia-induced VEGF expression and secretion but only in the A549 wildtype cell line. In the wildtype cell line, ionizing radiation alone induced hypoxia-dependent VEGF-expression but a strong dominant counteracting effect of patupilone was always observed when ionizing radiation was combined with patupilone, on the level of HIF-1α protein stability, VEGF-expression and VEGF-secretion. These results demonstrate that patupilone and ionizing radiation dysregulate hypoxia-induced stress responses, which might contribute to the potency of this promising, combined treatment modality.

The use of microtubule stabilizing agents (MSA) is a promising strategy for anti-cancer therapy alone and as part of combined treatment modalities with ionizing radiation. However MSA-provoked molecular and cellular processes including the regulation of intercellular, paracrine signaling pathways are far from clear. Here we investigated the interference of the novel, clinically relevant MSA patupilone (epothilone B) with the tumor-cell derived vascular endothelial growth factor (VEGF), which is most relevant for tumor angiogenesis. Low-dose, sub-nanomolar concentrations of patupilone specifically reduced hypoxia-driven stabilization of the transcription factor HIF-1α in the patupilone-sensitive lung adenocarcinoma cell line A549, but not in the mutant derivative cell line A549.EpoB40. Patupilone further reduced hypoxia-induced VEGF expression and secretion but only in the A549 wildtype cell line. In the wildtype cell line, ionizing radiation alone induced hypoxia-dependent VEGF-expression but a strong dominant counteracting effect of patupilone was always observed when ionizing radiation was combined with patupilone, on the level of HIF-1α protein stability, VEGF-expression and VEGF-secretion. These results demonstrate that patupilone and ionizing radiation dysregulate hypoxia-induced stress responses, which might contribute to the potency of this promising, combined treatment modality.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology
05 Vetsuisse Faculty > Veterinary Clinic > Department of Small Animals
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Patupilone, Ionizing Radiation, Angiogenesis, A549 Lung Adenocarcinoma Cells, Microtubules, VEGF, Hypoxia
Language:English
Date:2011
Deposited On:08 Feb 2011 14:36
Last Modified:05 Apr 2016 14:44
Publisher:Elsevier
ISSN:0169-5002
Publisher DOI:https://doi.org/10.1016/j.lungcan.2011.01.010
PubMed ID:21333376
Permanent URL: https://doi.org/10.5167/uzh-44998

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