Abstract |
The use of microtubule stabilizing agents (MSAs) 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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Authors | Carla Rohrer Bley, Katrin Orlowski, Polina Furmanova, Paul M J McSheehy, Martin Pruschy |
Journal | Lung cancer (Amsterdam, Netherlands)
(Lung Cancer)
Vol. 73
Issue 3
Pg. 294-301
(Sep 2011)
ISSN: 1872-8332 [Electronic] Ireland |
PMID | 21333376
(Publication Type: Journal Article)
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Copyright | Copyright © 2011 Elsevier Ireland Ltd. All rights reserved. |
Chemical References |
- Epothilones
- HIF1A protein, human
- Hypoxia-Inducible Factor 1, alpha Subunit
- Tubulin Modulators
- Vascular Endothelial Growth Factor A
- epothilone B
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Topics |
- Adenocarcinoma
(drug therapy, genetics, metabolism, pathology, radiotherapy)
- Cell Line, Tumor
- Combined Modality Therapy
- Epothilones
(pharmacology, therapeutic use)
- Gene Expression Regulation
(drug effects, radiation effects)
- Gene Expression Regulation, Neoplastic
- Humans
- Hypoxia-Inducible Factor 1, alpha Subunit
(genetics, metabolism)
- Lung Neoplasms
(drug therapy, genetics, metabolism, pathology, radiotherapy)
- Neovascularization, Pathologic
- Paracrine Communication
- Protein Stability
(drug effects)
- Radiation, Ionizing
- Tubulin Modulators
(pharmacology, therapeutic use)
- Vascular Endothelial Growth Factor A
(genetics, metabolism)
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