title: Regulation of VEGF-expression by patupilone and ionizing radiation in lung adenocarcinoma cells.
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.
authors.affiliation: Department of Radiation Oncology, University Hospital Zurich, Raemistr. 100, CH-8091 Zurich, Switzerland.
authors.forename: Carla
authors.initials: C
authors.lastname: Rohrer Bley
authors.forename: Katrin
authors.initials: K
authors.lastname: Orlowski
authors.forename: Polina
authors.initials: P
authors.lastname: Furmanova
authors.forename: Paul M J
authors.initials: PM
authors.lastname: McSheehy
authors.forename: Martin
authors.initials: M
authors.lastname: Pruschy
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D034261:Epothilones / Q000494:pharmacology* / Q000627:therapeutic use; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D009389:Neovascularization, Pathologic; D019899:Paracrine Communication; D055550:Protein Stability / Q000187:drug effects; D011839:Radiation, Ionizing; D050257:Tubulin Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*
chemical_list: D034261:Epothilones; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D050257:Tubulin Modulators; D042461:Vascular Endothelial Growth Factor A; C093788:epothilone B