Synergistic Growth Inhibitory Effects of the Dual Endothelin-1 Receptor Antagonist Bosentan on Pancreatic Stellate and Cancer Cells

Fitzner, Brit; Brock, Peter; Holzhüter, Stephanie-Anna; Nizze, H; Sparmann, Gisela; Emmrich, Jörg; Liebe, Stefan; Jaster, Robert

doi:10.1007/s10620-008-0366-z

Cited by 26 publications

(25 citation statements)

References 44 publications

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“…Extending our previous pilot study [11] , we observed that ET-1 induced a rapid and transient phosphorylation of two www.wjgnet.com Figure 2 Effects of ET-1 on PSC gene expression. PSC growing in 6-well plates were starved of serum for 1 h before they were stimulated with ET-1 (100 nmol/L) as indicated.…”

Section: Transduction Of the Et-1 Signal In Pscsupporting

confidence: 76%

“…www.wjgnet.com We and others have recently shown that ET-1 acts on PSCs in an autocrine fashion [11][12][13] . In agreement with a previous study [13] , we have now found that application of ET-1 to PSC cultures promotes migration.…”

Section: Discussionmentioning

confidence: 93%

“…Relative quantification of target cDNA levels by real-time PCR was performed in an ABI Prism 7000 sequence detection system (Applied Biosystems) using TaqMan™ Universal PCR Master Mix and the following Assay-on-Demand™ rat gene-specific fluorescently labelled TaqMan™ MGB probes: Rn00573960_g1 (CTGF), Rn00561129_m1 (ET-1), Rn00580432_m1 (IL-1β), Rn00561420_m1 (IL-6), Rn00572010_m1 (TGF-β1), and Rn01527838_g1 [hypoxanthine phosphoribosyl transferase (HPRT), used as house-keeping control gene]. The Custom TaqMan Gene Expression Assay specific for rat α-SMA (GenBank Accession Number: X06801) has been described previously [11] . Following the guidelines of the manufacturer, PCR was performed under the following conditions: 95℃ for 10 min, 50 cycles of 15 s at 95℃, 1 min at 60℃.…”

Section: Quantitative Reverse Transcriptase-pcr Using Real-time Taqmamentioning

confidence: 99%

“…Using bosentan, a clinically available dual ET-receptor antagonist targeting the two receptor types ETRA and ETRB, we recently observed inhibition of key functions of activated PSC, including proliferation and collagen synthesis [11] . When bosentan was applied to rats with chronic pancreatitis, at least a tendency towards a diminished disease progression was observed in a subgroup of animals with less severe disease.…”

Section: Introductionmentioning

confidence: 99%

“…The experiments were built on earlier reports by our group and others, which had suggested an autocrine loop of ET-1. Specifically, ET-1 was previously shown to activate extracellular signal-regulated kinases (ERK) 1 and 2, and to enhance PSC contraction and migration [11][12][13] . Our novel data deciphers ET-1 signalling in greater detail, and identifies, for the first time, target genes of ET-1 in PSC.…”

Section: Introductionmentioning

confidence: 99%

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Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

Jonitz¹,

Fitzner²,

Jaster³

2009

WJG

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AIM:To gain molecular insights into the expression and functions of endothelin-1 (ET-1) in pancreatic stellate cells (PSC). METHODS:PSCs were isolated from rat pancreas tissue, cultured, and stimulated with ET-1 or other extracellular mediators. Cell proliferation was assessed by measuring the incorporation of 5-bromo-2'-deoxyuridine into DNA and cell migration was studied in a transwell chamber assay. Gene expression at the level of mRNA was quantified by real-time polymerase chain reaction. Expression and phosphorylation of proteins were monitored by immunoblotting, applying an infrared imaging technology. ET-1 levels in cell culture supernatants were determined by an enzyme immunometric assay. To study DNA binding of individual transcription factors, electrophoretic mobility shift assays were performed.RESULTS: Among several mediators tested, transforming growth factor-β1 and tumour necrosis factor-α displayed the strongest stimulatory effects on ET-1 secretion. The cytokines induced binding of Smad3 and NF-κB, respectively, to oligonucleotides derived from the ET-1 promoter, implicating both transcription factors in the induction of ET-1 gene expression. In accordance with previous studies, ET-1 was found to stimulate migration but not proliferation of PSC. Stimulation of ET-1 receptors led to the activation of two distinct mitogen-activated protein kinases, p38 and extracellular signal-regulated kinases (ERK)1/2, as well as the transcription factor activator protein-1. At the mRNA level, enhanced expression of the PSC activation marker, α-smooth muscle actin and two proinflammatory cytokines, interleukin (IL)-1β and IL-6, was observed. CONCLUSION:This study provides novel lines of evidence for profibrogenic and proinflammatory actions of ET-1 in the pancreas, encouraging further studies with ET-1 inhibitors in chronic pancreatitis.

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Section: Transduction Of the Et-1 Signal In Pscsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 93%

Section: Quantitative Reverse Transcriptase-pcr Using Real-time Taqmamentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

Jonitz¹,

Fitzner²,

Jaster³

2009

WJG

Self Cite

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Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

Voutouri

Panagi

Mpekris

et al. 2021

Advanced Therapeutics

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Immunotherapy efficacy depends on T cell trafficking to tumors and migrating to malignant cells to kill them. One barrier to T cell homing is the tumor blood vessel wall, which inhibits T cell attachment and transmigration through the endothelin B receptor, but antagonizing this receptor has not led to a clinically approved drug. One reason may be tumor hypo‐perfusion, which limits the area of perfused vessels for T cell attachment. If collapsed vessels can be decompressed and re‐perfused by alleviating tumor stiffness, then endothelin B receptor antagonism can improve immunotherapy. Here, it is tested whether the nonselective endothelin receptor blocker, bosentan, by simultaneously interfering with endothelin A receptor induced fibrosis, can normalize the tumor microenvironment thereby acting as a “mechanotherapeutic.” Tumor stiffness is monitored with ultrasound elastography and nanomechanical properties with atomic force microscopy to find an optimal dose, which reprograms cancer‐associated fibroblasts resulting in reduced collagen thereby decompressing vessels. Through this mechanism, T cell association with tumor vessels increases and immunosuppressive hypoxia is reduced. Additionally, bosentan increases the CD8+ T cells proliferating fraction. Ultrasound stiffness measurements correlate well with response to immunotherapy, suggesting the potential role of ultrasound elastography as a predictive biomarker of response to immune checkpoint inhibitors.

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Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans

Jansson

Carlsson

2019

Comprehensive Physiology

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The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5‐ to 10‐fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo‐acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799‐837, 2019.

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Synergistic Growth Inhibitory Effects of the Dual Endothelin-1 Receptor Antagonist Bosentan on Pancreatic Stellate and Cancer Cells

Cited by 26 publications

References 44 publications

Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

Molecular determinants of the profibrogenic effects of endothelin-1 in pancreatic stellate cells

Endothelin Inhibition Potentiates Cancer Immunotherapy Revealing Mechanical Biomarkers Predictive of Response

Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans

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