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

Bley, Carla Rohrer; Orlowski, Katrin; Furmanova, Polina; McSheehy, Paul M.J.; Pruschy, Martin

doi:10.1016/j.lungcan.2011.01.010

Cited by 10 publications

(12 citation statements)

References 22 publications

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“…Of interest, we previously demonstrated that patupilone is as potent under normoxic as under hypoxic conditions and strongly sensitizes for ionizing radiation in particular in vivo . This coincides with interference of patupilone with the HIF-transcriptome, previously demonstrated for hypoxia-induced VEGF secretion [38]. Thus, the anti-metastatic effect of patupilone and related epothilone-derivatives, as characterized in other studies, might in part be due to reduced LOX secretion under hypoxia in patupilone-treated xenografts [42,43].…”

Section: Discussionsupporting

confidence: 80%

“…To investigate a putative counteracting effect of patupilone on IR-induced LOX-secretion, A459 tumor cells were pretreated with patupilone 24 hours prior to irradiation and LOX-secretion in CM was measured over 16-20 hours after irradiation. No change in basal or IR-induced LOX secretion was observed in CM derived from un-treated or pretreated cells with 0.5 nM patupilone, a dose previously shown to inhibit IR-induced VEGF and MMP-secretion in A549 cells (Figure 3A) [11,38]. These results suggest potentially different mechanisms governing LOX and VEGF or MMP secretion in response to IR.Even though patupilone did not affect IR-induced LOX secretion, we investigated hypoxia-induced LOX secretion to be regulated by patupilone.…”

Section: Resultsmentioning

confidence: 99%

“…The microtubule stabilizing agent patupilone has previously been shown to abrogate hypoxia-induced protein expression, to sensitize for radiotherapy and to inhibit IR-induced VEGF and MMP secretion [11,34-38]. Thus, patupilone could potentially be used in combination with IR to abrogate any IR-induced LOX-related invasive or malignant phenotype.…”

Section: Resultsmentioning

confidence: 99%

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Ionizing radiation induces tumor cell lysyl oxidase secretion

et al. 2014

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BackgroundIonizing radiation (IR) is a mainstay of cancer therapy, but irradiation can at times also lead to stress responses, which counteract IR-induced cytotoxicity. IR also triggers cellular secretion of vascular endothelial growth factor, transforming growth factor β and matrix metalloproteinases, among others, to promote tumor progression. Lysyl oxidase is known to play an important role in hypoxia-dependent cancer cell dissemination and metastasis. Here, we investigated the effects of IR on the expression and secretion of lysyl oxidase (LOX) from tumor cells.MethodsLOX-secretion along with enzymatic activity was investigated in multiple tumor cell lines in response to irradiation. Transwell migration assays were performed to evaluate invasive capacity of naïve tumor cells in response to IR-induced LOX. In vivo studies for confirming IR-enhanced LOX were performed employing immunohistochemistry of tumor tissues and ex vivo analysis of murine blood serum derived from locally irradiated A549-derived tumor xenografts.ResultsLOX was secreted in a dose dependent way from several tumor cell lines in response to irradiation. IR did not increase LOX-transcription but induced LOX-secretion. LOX-secretion could not be prevented by the microtubule stabilizing agent patupilone. In contrast, hypoxia induced LOX-transcription, and interestingly, hypoxia-dependent LOX-secretion could be counteracted by patupilone. Conditioned media from irradiated tumor cells promoted invasiveness of naïve tumor cells, while conditioned media from irradiated, LOX- siRNA-silenced cells did not stimulate their invasive capacity. Locally applied irradiation to tumor xenografts also increased LOX-secretion in vivo and resulted in enhanced LOX-levels in the murine blood serum.ConclusionsThese results indicate a differential regulation of LOX-expression and secretion in response to IR and hypoxia, and suggest that LOX may contribute towards an IR-induced migratory phenotype in sublethally-irradiated tumor cells and tumor progression.

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Section: Discussionsupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Ionizing radiation induces tumor cell lysyl oxidase secretion

et al. 2014

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“…We recently demonstrated that patupilone counteracts stress-induced VEGF expression and secretion from patupilone-sensitive tumor cells [19]. Furthermore, MSA could disturb the secretion of matrix metalloproteinase thereby affecting the tumor microenvironment (see below) [20-22].…”

Section: Introductionmentioning

confidence: 99%

The microtubule stabilizer patupilone counteracts ionizing radiation-induced matrix metalloproteinase activity and tumor cell invasion

Furmanova-Hollenstein

Broggini-Tenzer

Eggel

et al. 2013

Radiat Oncol

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BackgroundIonizing radiation (IR) in combination with microtubule stabilizing agents (MSA) is a promising combined treatment modality. Supra-additive treatment responses might result from direct tumor cell killing and cooperative indirect, tumor cell-mediated effects on the tumor microenvironment. Here we investigated deregulation of matrix metalloproteinase (MMP) activity, as an important component of the tumor microenvironment, by the combined treatment modality of IR with the clinically relevant MSA patupilone.MethodsExpression, secretion and activity of MMPs and related tissue inhibitors of metalloproteinases (TIMPs) were determined in cell extracts and conditioned media derived from human fibrosarcoma HT1080 and human glioblastoma U251 tumor cells in response to treatment with IR and the MSA patupilone. Treatment-dependent changes of the invasive capacities of these tumor cell lines were analysed using a Transwell invasion assay. Control experiments were performed using TIMP-directed siRNA and TIMP-directed inhibitory antibodies.ResultsEnzymatic activity of secreted MMPs was determined after treatment with patupilone and irradiation in the human fibrosarcoma HT1080 and the human glioblastoma U251 tumor cell line. IR enhanced the activity of secreted MMPs up to 2-fold and cellular pretreatment with low dose patupilone (0.05-0.2 nM) counteracted specifically the IR-induced MMP activity. The cell invasive capacity of HT1080 and U251 cells was increased after irradiation with 2 Gy by 30% and 50%, respectively, and patupilone treatment completely abrogated IR-induced cell invasion. Patupilone did not alter the level of MMP expression, but interestingly, the protein level of secreted TIMP-1 and TIMP-2 was lower after combined treatment than after irradiation treatment alone. Furthermore, siRNA depletion of TIMP-1 or TIMP-2 prevented IR-mediated induction of MMP activity and cell invasion.ConclusionsThese results indicate that patupilone counteracts an IR-induced MMP activation process by the reduction of secreted TIMP-1 and TIMP-2 proteins, which are required for activation of MMPs. Since IR-induced MMP activity could contribute to tumor progression, treatment combination of IR with patupilone might be of great clinical benefit for tumor therapy.

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“…Furthermore, patupilone is known to have anti-angiogenic effects via paracrine activity at the level of VEGF secretion and other factors [18,19]. This anti-angiogenic activity can be detected by magnetic resonance imaging (MRI) [20,21,22].…”

Section: Introductionmentioning

confidence: 99%

Patupilone (Epothilone B) for Recurrent Glioblastoma: Clinical Outcome and Translational Analysis of a Single-Institution Phase I/II Trial

Oehler

Frei²,

Rushing³

et al. 2012

Oncology

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Background: Patients with glioblastoma (GBM) inevitably develop recurrent or progressive disease after initial multimodal treatment and have a median survival of 6–9 months from time of progression. To date, there is no accepted standard treatment for GBM relapse or progression. Patupilone (EPO906) is a novel natural microtubule-stabilizing cytotoxic agent that crosses the blood-brain barrier and has been found to have preclinical activity in glioma models. Methods: This is a single-institution, early-phase I/II trial of GBM patients with tumor progression who qualified for second surgery with the goal of evaluating efficacy and safety of the single-agent patupilone (10 mg/m², every 3 weeks). Patients received patupilone 1 week prior to second surgery and every 3 weeks thereafter until tumor progression or toxicity. Primary end points were progression-free survival (PFS) and overall survival (OS) at 6 months as well as patupilone concentration in tumor tissue. Secondary end points were toxicity, patupilone concentration in plasma and translational analyses for predictive biomarkers. Results: Nine patients with a mean age of 54.6 ± 8.6 years were recruited between June 2008 and April 2010. Median survival and 1-year OS after second surgery were 11 months (95% CI, 5–17 months) and 45% (95% CI, 14–76), respectively. Median PFS was 1.5 months (95% CI, 1.3–1.7 months) and PFS6 was 22% (95% CI, 0–46), with 2 patients remaining recurrence-free at 9.75 and 22 months. At the time of surgery, the concentration of patupilone in tumor tissue was 30 times higher than in the plasma. Tumor response was not predictable by the tested biomarkers. Treatment was generally well tolerated with no hematological, but cumulative, though reversible sensory neuropathy grade ≤3 was seen in 2 patients (22%) at 8 months and grade 4 diarrhea in the 2nd patient (11%). Non-patupilone-related peri-operative complications occurred in 2 patients resulting in discontinuation of patupilone therapy. There were no neurocognitive changes 3 months after surgery compared to baseline. Conclusions: In recurrent GBM, patupilone can be given safely pre- and postoperatively. The drug accumulates in the tumor tissue. The treatment results in long-term PFS in some patients. Patupilone represents a valuable novel compound which deserves further evaluation in combination with radiation therapy in patients with GBM.

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

Cited by 10 publications

References 22 publications

Ionizing radiation induces tumor cell lysyl oxidase secretion

Ionizing radiation induces tumor cell lysyl oxidase secretion

The microtubule stabilizer patupilone counteracts ionizing radiation-induced matrix metalloproteinase activity and tumor cell invasion

Patupilone (Epothilone B) for Recurrent Glioblastoma: Clinical Outcome and Translational Analysis of a Single-Institution Phase I/II Trial

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