scholarly journals Genomic assessment of a multikinase inhibitor, sorafenib, in a rodent model of pulmonary hypertension

2008 ◽  
Vol 33 (2) ◽  
pp. 278-291 ◽  
Author(s):  
Liliana Moreno-Vinasco ◽  
Mardi Gomberg-Maitland ◽  
Michael L. Maitland ◽  
Ankit A. Desai ◽  
Patrick A. Singleton ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Antineoplastic Agent ◽  
Mapk Cascade ◽  
Molecular Signature ◽  
Vegf Receptor ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Cancer Pathology ◽  
Model Combining ◽  
Normoxic Control

Pulmonary hypertension (PH) and cancer pathology share growth factor- and MAPK stress-mediated signaling pathways resulting in endothelial and smooth muscle cell dysfunction and angioproliferative vasculopathy. In this study, we assessed sorafenib, an antineoplastic agent and inhibitor of multiple kinases important in angiogenesis [VEGF receptor (VEGFR)-1–3, PDGF receptor (PDGFR)-β, Raf-1 kinase] as a potential PH therapy. Two PH rat models were used: a conventional hypoxia-induced PH model and an augmented PH model combining dual VEGFR-1 and -2 inhibition (SU-5416, single 20 mg/kg injection) with hypoxia. In addition to normoxia-exposed control animals, four groups were maintained at 10% inspired O2fraction for 3.5 wk (hypoxia/vehicle, hypoxia/SU-5416, hypoxia/sorafenib, and hypoxia/SU-5416/sorafenib). Compared with normoxic control animals, rats exposed to hypoxia/SU-5416 developed hemodynamic and histological evidence of severe PH while rats exposed to hypoxia alone displayed only mild elevations in hemodynamic values (pulmonary vascular and right ventricular pressures). Sorafenib treatment (daily gavage, 2.5 mg/kg) prevented hemodynamic changes and demonstrated dramatic attenuation of PH-associated vascular remodeling. Compared with normoxic control rats, expression profiling (Affymetrix platform) of lung RNA obtained from hypoxia [false discovery rate (FDR) 6.5%]- and hypoxia/SU-5416 (FDR 1.6%)-challenged rats yielded 1,019 and 465 differentially regulated genes (fold change >1.4), respectively. A novel molecular signature consisting of 38 differentially expressed genes between hypoxia/SU-5416 and hypoxia/SU-5416/sorafenib (FDR 6.7%) was validated by either real-time RT-PCR or immunoblotting. Finally, immunoblotting studies confirmed the upregulation of the MAPK cascade in both PH models, which was abolished by sorafenib. In summary, sorafenib represents a novel potential treatment for severe PH with the MAPK cascade a potential canonical target.

scholarly journals Longitudinal Circulating Levels of miR-23b-3p, miR-126-3p and lncRNA GAS5 in HCC Patients Treated with Sorafenib

Biomedicines ◽  
2021 ◽  
Vol 9 (7) ◽  
pp. 813
Author(s):  
Michele Manganelli ◽  
Ilaria Grossi ◽  
Manuela Ferracin ◽  
Paola Guerriero ◽  
Massimo Negrini ◽  
...  
Keyword(s):  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Healthy Individuals ◽  
Roc Curve Analysis ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
The Third ◽  
Circulating Levels ◽  
Systemic Drug

Human hepatocellular carcinoma (HCC) is the most frequent primary tumor of the liver and the third cause of cancer-related deaths. The multikinase inhibitor sorafenib is a systemic drug for unresectable HCC. The identification of molecular biomarkers for the early diagnosis of HCC and responsiveness to treatment are needed. In this work, we performed an exploratory study to investigate the longitudinal levels of cell-free long ncRNA GAS5 and microRNAs miR-126-3p and -23b-3p in a cohort of 7 patients during the period of treatment with sorafenib. We used qPCR to measure the amounts of GAS5 and miR-126-3p and droplet digital PCR (ddPCR) to measure the levels of miR-23b-3p. Patients treated with sorafenib displayed variable levels of GAS5, miR-126-3p and miR-23b-3p at different time-points of follow-up. miR-23b-3p was further measured by ddPCR in 37 healthy individuals and 25 untreated HCC patients. The amount of miR-23b-3p in the plasma of untreated HCC patients was significantly downregulated if compared to healthy individuals. The ROC curve analysis underlined its diagnostic relevance. In conclusion, our results highlight a potential clinical significance of circulating miR-23b-3p and an exploratory observation on the longitudinal plasmatic levels of GAS5, miR-126-3p and miR-23b-3p during sorafenib treatment.

Intrauterine hypertension decreases lung VEGF expression and VEGF inhibition causes pulmonary hypertension in the ovine fetus

2003 ◽  
Vol 284 (3) ◽  
pp. L508-L517 ◽  
Author(s):  
Theresa R. Grover ◽  
Thomas A. Parker ◽  
Jeanne P. Zenge ◽  
Neil E. Markham ◽  
John P. Kinsella ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Protein Content ◽  
Ductus Arteriosus ◽  
Late Gestation ◽  
Receptor Protein ◽  
Vegf Receptor ◽  
Fetal Life ◽  
Vegf Expression ◽  
Vegf Signaling ◽  
Vegf Inhibition

Although vascular endothelial growth factor (VEGF) plays a vital role in lung vascular growth in the embryo, its role in maintaining endothelial function and modulating vascular structure during late fetal life has not been studied. We hypothesized that impaired lung VEGF signaling causes pulmonary hypertension, endothelial dysfunction, and structural remodeling before birth. To determine whether lung VEGF expression is decreased in an experimental model of persistent pulmonary hypertension of the newborn (PPHN), we measured lung VEGF and VEGF receptor protein content from fetal lambs 7–10 days after ductus arteriosus ligation (132–140 days gestation; term = 147 days). In contrast with the surge in lung VEGF expression during late gestation in controls, chronic intrauterine pulmonary hypertension reduced lung VEGF expression by 78%. To determine whether VEGF inhibition during late gestation causes pulmonary hypertension, we treated fetal lambs with EYE001, an aptamer that specifically inhibits VEGF165. Compared with vehicle controls, EYE001 treatment elevated pulmonary artery pressure and pulmonary vascular resistance by 22 and 50%, respectively, caused right ventricular hypertrophy, and increased wall thickness of small pulmonary arteries. EYE001 treatment reduced lung endothelial nitric oxide synthase protein content by 50% and preferentially impaired the pulmonary vasodilator response to ACh, an endothelium-dependent agent. We conclude that chronic intrauterine pulmonary hypertension markedly decreases lung VEGF expression and that selective inhibition of VEGF165 mimics the structural and physiological changes of experimental PPHN. We speculate that hypertension downregulates VEGF expression in the developing lung and that impaired VEGF signaling may contribute to the pathogenesis of PPHN.

scholarly journals Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin

2010 ◽  
Vol 299 (6) ◽  
pp. L735-L748 ◽  
Author(s):  
Jen-Ruey Tang ◽  
Gregory J. Seedorf ◽  
Vincent Muehlethaler ◽  
Deandra L. Walker ◽  
Neil E. Markham ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Vascular Wall ◽  
Vessel Density ◽  
Interactive Effects ◽  
Vegf Receptor ◽  
Lung Growth ◽  
Sprague Dawley ◽  
Infant Rats ◽  
Lung Structure ◽  
Neonatal Hyperoxia

To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O2, 80% O2 at Denver's altitude, ∼65% O2 at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O2 rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (≥95% O2 at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy.

Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure

2002 ◽  
Vol 283 (3) ◽  
pp. L555-L562 ◽  
Author(s):  
Timothy D. Le Cras ◽  
Neil E. Markham ◽  
Rubin M. Tuder ◽  
Norbert F. Voelkel ◽  
Steven H. Abman
Keyword(s):  
Pulmonary Hypertension ◽  
Vegf Receptor ◽  
Newborn Rats ◽  
Long Term Effects ◽  
Adult Rats ◽  
Rat Pups ◽  
Lung Structure ◽  
Vegfr Inhibitor ◽  
And Function

To determine whether disruption of vascular endothelial growth factor (VEGF)-VEGF receptor (VEGFR) signaling in the newborn has long-term effects on lung structure and function, we injected 1-day-old newborn rat pups with a single dose of Su-5416, a VEGFR inhibitor, or vehicle (controls). Lungs from infant (3-wk-old) and adult (3- to 4-mo-old) rats treated with Su-5416 as newborns showed reductions in arterial density (82 and 31%, respectively) and alveolar counts (45 and 29%) compared with controls. Neonatal treatment with Su-5416 increased right ventricle weight to body wt ratios (4.2-fold and 2.0-fold) and pulmonary arterial wall thickness measurements (2.7-fold and 1.6-fold) in infant and adult rats, respectively, indicating marked pulmonary hypertension. We conclude that treatment of newborn rats with the VEGFR inhibitor Su-5416 impaired pulmonary vascular growth and postnatal alveolarization and caused pulmonary hypertension and that these effects were long term, persisting well into adulthood.

scholarly journals C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade

Life Sciences ◽  
2011 ◽  
Vol 89 (13-14) ◽  
pp. 460-466 ◽  
Author(s):  
Brian Casserly ◽  
Jeffrey M. Mazer ◽  
Alexander Vang ◽  
Elizabeth O. Harrington ◽  
James R. Klinger ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Natriuretic Peptide ◽  
Vegf Receptor ◽  
Receptor Blockade

scholarly journals VEGF mediates fat embolism-induced acute lung injury via VEGF receptor 2 and the MAPK cascade

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Chin-Kuo Lin ◽  
Yu-Hao Lin ◽  
Tai-Chun Huang ◽  
Chung-Sheng Shi ◽  
Cheng-Ta Yang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Fat Embolism ◽  
Mapk Cascade ◽  
Vegf Receptor

scholarly journals Elucidation of the Molecular Mechanisms Underlying Sorafenib-Induced Hepatotoxicity

2020 ◽  
Vol 2020 ◽  
pp. 1-10 ◽  
Author(s):  
Abdullah F. AlAsmari ◽  
Nemat Ali ◽  
Fawaz AlAsmari ◽  
Wael A. AlAnazi ◽  
Faleh Alqahtani ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Molecular Mechanisms ◽  
Oxidative Stress Marker ◽  
Multikinase Inhibitor ◽  
Male Adult ◽  
Sorafenib Treatment ◽  
Apoptotic Pathways ◽  
Orally Active ◽  
Saline Vehicle

Sorafenib is a small, orally-active multikinase inhibitor that is most frequently used for the management of renal cell carcinoma, hepatocellular carcinoma, and radioactive iodine-resistant thyroid carcinoma. However, recent reports have associated sorafenib with hepatotoxicity that can limit its clinical application, although the mechanism of hepatotoxicity is still to be elucidated. Thus, our study was designed to explore the molecular mechanisms underlying sorafenib-induced hepatotoxicity in an in vivo model. Twenty male adult Wistar rats were randomly placed into two groups; the first group received an oral dose of normal saline (vehicle), and the second received sorafenib (30 mg/kg) once daily for twenty-one consecutive days. After twenty-one days, liver tissues and blood samples were used for gene expression, protein expression, and biochemical analysis. Sorafenib treatment resulted in markedly increased levels of alanine aminotransferase and alkaline phosphatase, which indicate the presence of liver damage. Additionally, sorafenib administration induced the inflammatory and oxidative stress marker NF-κB-p65, while antioxidant enzymes were attenuated. Moreover, sorafenib caused upregulation of both gene and protein for the apoptotic markers cleaved Caspase-3, Bax, and Bid, and downregulation of the antiapoptotic protein Bcl-2. In conclusion, our findings suggest that sorafenib administration is associated with hepatotoxicity, which might be due to the activation of oxidative stress and apoptotic pathways.

Abstract 2621: C-type Natriuretic Peptide Attenuates Vascular Remodeling In Severe Pulmonary Hypertension

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Jeffrey M Mazer ◽  
Brian Casserly ◽  
Sharon Rounds ◽  
Gaurav Choudhary
Keyword(s):  
Pulmonary Hypertension ◽  
Natriuretic Peptide ◽  
Vascular Remodeling ◽  
Right Heart Catheterization ◽  
Heart Catheterization ◽  
Vegf Receptor ◽  
Severe Pulmonary Hypertension ◽  
Sprague Dawley ◽  
Pulmonary Vascular Remodeling ◽  
Hypertrophic Response

Pulmonary vascular remodeling and endothelial proliferation are important pathophysiological processes contributing to increased vascular resistance seen with pulmonary hypertension (PH). C-type natriuretic peptide (CNP) is an endothelium derived natriuretic peptide that has been shown to have anti-inflammatory, anti-mitogenic and anti-proliferative actions. However, its role in modulating severe PH is not known. We hypothesized that CNP will attenuate severe PH through its effect on pulmonary vascular remodeling. In order to test our hypothesis we chose to study the effect of continuous infusion of CNP, delivered by an osmotic pump, in a rat model of severe PH. This model combines the use of a VEGF receptor blocker, SU5416 (SU), and hypoxia to induce severe PH and plexiform lesions. Adult male Sprague Dawley rats were implanted with osmotic pumps to deliver CNP or vehicle for three weeks. Subsequently they received a single dose of SU or diluant and were placed in either normoxic or hypoxic (10% FiO 2 ) environment for 3 wks. the animals then underwent echocardiogram, right heart catheterization, and carotid catheterization to evaluate right ventricle (RV) function, RV mass, and RV pressure (RVP). The lungs were fixed and evaluated for vascular remodeling using H&E staining and immunohistochemistry. Rats exposed to hypoxia alone developed moderate PH, while animals given SU and exposed to hypoxia developed severe PH (RVP (mmHg)- Normoxia: 27±1; Hypoxia: 79±6; Hypoxia+SU: 92±3). RV hypertrophic response mirrored the RVP in each group. Animals with severe PH receiving low dose CNP (0.75μg/hr) had increased RV mass and RVP, similar to vehicle treated animals, but demonstrated a 19% reduction in the microvascular wall thickness (p<0.05 compared to vehicle). Upon treatment with a higher dose of CNP (2.25μg/hr), animals demonstrated a significant reduction in RVP in the severe PH group (76±5 mmHg), as compared to vehicle treated animals (95±6 mmHg, p<0.05). CNP attenuates severe pulmonary hypertension likely via its effects on microvascular remodeling.

IGF1R Inhibition Induces Apoptosis in Chronic Lymphocytic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3864-3864
Author(s):  
Niuscha Yaktapour ◽  
Rudolf Uebelhart ◽  
Christine Dierks ◽  
Meike Burger ◽  
Dietmar Pfeifer ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Growth Factor ◽  
Chronic Lymphocytic Leukemia ◽  
Growth Factor Receptor ◽  
Lymphocytic Leukemia ◽  
Multikinase Inhibitor ◽  
Sorafenib Treatment ◽  
Igf1r Inhibitor ◽  
Induced Apoptosis

Abstract Abstract 3864 Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of monoclonal B lymphocytes. For decades, nucleoside analogs, alkylating agents, and immunotherapeutics have remained the mainstay in treating this disease. Despite major advances in this field, CLL remains incurable with standard therapy. In recent years, preclinical and early clinical data on the use of kinase inhibitors have sparked new hope in the treatment of CLL. The multikinase inhibitor sorafenib, targeting RAF, platelet-derived growth factor receptor (PDGFR), KIT, FMS-like tyrosine kinase 3 (FLT3), and vascular endothelial growth factor receptor (VEGFR), has been approved for the treatment of renal cell carcinoma and hepatocellular carcinoma. Recent studies suggested that CLL cells might be also susceptible to this compound, however the precise mode of action in CLL cells remains elusive. In this study, we identified the Insulin-like growth factor receptor-I (IGF1R) pathway as novel target of sorafenib inducing cell death in CLL cells. Treatment with 10 μM of sorafenib significantly increased apoptosis in primary CLL cells as determined by AnnexinV/PI staining via flow cytometry. Commensurate with its RAF inhibiting properties, the apoptotic effect of sorafenib was accompanied with ERK pathway inhibition. Moreover, sorafenib treatment decreased phosphorylation of SRC and AKT, molecules implicated with IGF1R and insulin receptor (IR) signaling. Interestingly, the latter were strongly expressed in primary CLL cells compared with healthy B cells. Similar to sorafenib, 24 hour treatment of CLL cells with the three structurally distinct IGF1R inhibitors Picropodophyllin, AG1024, and Linsitinib significantly increased apoptosis compared with vehicle control resulting in decreased phophorylation of MEK, ERK, SRC, and AKT. Sorafenib and the IGF1R inhibitor AG1024 also downregulated the expression of IGF1R on CLL cells but not on healthy B cells. To test whether sorafenib modulates IGF-1 binding and thereby influences the IGF1R activation, we biotinylated recombinant IGF-1 and tested its binding to the IGF1R via flow cytometry. We observed a reduced IGF-1 binding after sorafenib treatment. IGF-1 binding after treatment with different IGF1R inhibitors was performed as an internal control. In order to further establish the functional relevance of IGF1R expression in CLL, we performed IGF1R specific and non-silencing siRNA experiments in primary CLL cells. In line with our previous results, IGF1R knockdown resulted in a significant decrease of cell viability and in downregulation of RAF-1 expression, and MEK, ERK, SRC, and AKT phosphorylation. The stromal microenvironment protects CLL cells from spontaneous and drug-induced apoptosis. Sorafenib, AG1024, and Picropodophyllin counteracted the protective effect of microenvironmental factors simulated by the presence of the murine stromal cell line M210B4, the chemokine CXCL12, and the integrin CD49d. Finally, we used the Eμ-Tcl1 transgenic mouse model to validate these results in vivo. Male and female mice (n=8) were treated with 25 mg/kg of the IGF1R inhibitor Linsitinib per oral gavage for 7 days and the amount of CD5/CD19 positive cells was determined flow cytometrically at different time points. We observed a reduction of CD5/CD19-positive cells by 26,1% and 23,2% after 4 and 8 days of treatment, respectively. Our results provide a novel mechanism of action of the multikinase inhibitor sofarenib in CLL cells by blocking IGF1R mediated signaling. IGF1R inhibition by itself induced apoptosis in CLL cells in vitro and in vivo, thus identifying IGF1R as promising target for therapeutic approaches and proposing IGF1R inhibitors for clinical assessment in the therapy of CLL. Disclosures: No relevant conflicts of interest to declare.

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