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nvp-aew541

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Journal Articles
Mol Cancer Ther (2021) 20 (9): 1521–1532.
Published: 01 September 2021
..., cabozantinib, AEE788, anlotinib, regorafenib, tivozanib, axitinib, PTK787, vandetanib KIT Kit proto-oncogene RTK Pazopanib, nintedanib, PLX3397 IGF1R Insulin like growth factor 1 receptor RTK NVP-AEW541 a CSF1R Colony-stimulating factor 1 receptor RTK PLX3397 ALK Anaplastic...
Journal Articles
Series: Author Choice
Mol Cancer Ther (2020) 19 (4): 1059–1069.
Published: 02 April 2020
... ). Our results showed reduced expression of AR-V7–regulated genes following combination treatment, consistent with the previous findings that inhibition of IGF-1R by the tyrosine kinase inhibitors NVP-AEW541 and AG1024 led to downregulation of AR-V7 transcriptional activity in prostate cancer cells ( 33...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2009) 8 (12_Supplement): B253.
Published: 10 December 2009
... by the signal transducer and activator of transcription 3 (Stat3) in this pathway; and c) the ability of the IGF1R inhibitor NVPAEW541 (Novartis Pharma, Basel, CH) to disrupt this pathway. We show that activation of IGF1R by its ligand IGF1 causes Stat3 activation, increased levels of HIF1α and increased...
Journal Articles
Series: Author Choice
Mol Cancer Ther (2017) 16 (10): 2130–2143.
Published: 02 October 2017
...   J , Zimmermann   J , et al   In vivo antitumor activity of NVP-AEW541-A novel, potent, and selective inhibitor of the IGF-IR kinase . Cancer Cell   2004 ; 5 : 231 – 9 . 19. Wang   Y , Wang   L , Guan   S , Cao   W , Wang   H , Chen   Z , et al   Novel ALK inhibitor...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2017) 16 (4): 705–716.
Published: 02 April 2017
... receptor inhibitor NVP-AEW541 . Neuro-Oncol   2010 ; 12 : 967 – 75 . 27. Cully   M , You   H , Levine   AJ , Mak   TW .  Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis . Nat Rev Cancer   2006 ; 6 : 184 – 92 . 28. Pollak   M...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2016) 15 (11): 2722–2732.
Published: 01 November 2016
... , Hu   CJ .  STAT3 and HIF1alpha cooperatively activate HIF1 target genes in MDA-MB-231 and RCC4 cells . Oncogene   2014 ; 33 : 1670 – 9 . 57. Gariboldi   MB , Ravizza   R , Monti   E .  The IGFR1 inhibitor NVP-AEW541 disrupts a pro-survival and pro-angiogenic IGF-STAT3-HIF1 pathway...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2016) 15 (7): 1545–1556.
Published: 05 July 2016
... to 1.4 μmol/L at 2 μmol/L OSI-906 ( Fig. 2A ). Analogous results were obtained using the IGF1R inhibitor NVP-AEW541 (Supplementary Fig. S1). The sensitization to PI3K inhibition by OSI-906 resulted in a pronounced reduction in colony outgrowth after prolonged culture ( Fig. 2B ). Figure 2...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2015) 14 (12): 2687–2699.
Published: 06 December 2015
... for these lower IC50 values in ER+ breast cancer. If the latter is the case, IGF-IR could be one such targeted kinase in ER+ breast cancer. In fact, in another study that tested IGF-IR inhibitor NVP-AEW541 for breast cancer cells, MCF7 cells showed the highest sensitivity to IGF...
Includes: Supplementary data
Journal Articles
Mol Cancer Ther (2011) 10 (8): 1407–1418.
Published: 08 August 2011
... as constitutive receptor activation in pGBM cell lines. To evaluate the therapeutic potential of strategies targeting the receptor, we have carried out in vitro and in vivo preclinical studies using the specific IGF1R inhibitor NVP-AEW541. A modest inhibitory effect was seen in vitro...
Includes: Supplementary data
Images
Expression profiling of KNS42 cells treated with <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> highlights gene...
Published: 08 August 2011
Figure 4. Expression profiling of KNS42 cells treated with NVP-AEW541 highlights gene signatures associated with a PI3K-mediated cell-cycle arrest. A, heat map showing expression of genes associated with the G1–S-phase transition of the cell cycle in KNS42 cells treated with 5× GI50 NVP-AEW541 for 1, 6, or 24 hours. Genes are colored according to global, not relative, expression values. B, GSEA of NVP-AEW541–treated KNS42 cells identified numerous groups of genes associated with the cell cycle. Enrichment score plots show strong negative correlation (downregulation) with treatment with inhibitors given. C, gene ontology analysis using the DAVID bioinformatics tool. A decrease in expression of numerous genes associated with processes such as cell-cycle control and DNA replication are seen in KNS42 cells treated with NVP-AEW541. Bars represent fold enrichment of the most significant gene ontology groups, colored by Bonferroni-corrected P values. D, Connectivity Map analysis of NVP-AEW541–induced gene signatures in KNS42 cells. The bar view is constructed from 6,100 horizontal lines representing individual treatment instances ordered by their corresponding enrichment with the NVP-AEW541 signature (positive, green; negative, red; no enrichment, gray). All instances involving the PI3K inhibitors LY294002 and wortmannin are colored black, with corresponding highest scoring treatment instances given in the table. Figure 4. Expression profiling of KNS42 cells treated with NVP-AEW541 highlights gene signatures associated with a PI3K-mediated cell-cycle arrest. A, heat map showing expression of genes associated with the G1–S-phase transition of the cell cycle in KNS42 cells treated with 5× GI50 NVP-AEW541 for 1, 6, or 24 hours. Genes are colored according to global, not relative, expression values. B, GSEA of NVP-AEW541–treated KNS42 cells identified numerous groups of genes associated with the cell cycle. Enrichment score plots show strong negative correlation (downregulation) with treatment with inhibitors given. C, gene ontology analysis using the DAVID bioinformatics tool. A decrease in expression of numerous genes associated with processes such as cell-cycle control and DNA replication are seen in KNS42 cells treated with NVP-AEW541. Bars represent fold enrichment of the most significant gene ontology groups, colored by Bonferroni-corrected P values. D, Connectivity Map analysis of NVP-AEW541–induced gene signatures in KNS42 cells. The bar view is constructed from 6,100 horizontal lines representing individual treatment instances ordered by their corresponding enrichment with the NVP-AEW541 signature (positive, green; negative, red; no enrichment, gray). All instances involving the PI3K inhibitors LY294002 and wortmannin are colored black, with corresponding highest scoring treatment instances given in the table. More
Images
Chemical structures of <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span>, imatinib, TMZ, LY294002, and wortmannin....
Published: 08 August 2011
Figure 1. Chemical structures of NVP-AEW541, imatinib, TMZ, LY294002, and wortmannin. Figure 1. Chemical structures of NVP-AEW541, imatinib, TMZ, LY294002, and wortmannin. More
Images
Treatment with <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> overcomes resistance to TMZ and induces autophagy...
Published: 08 August 2011
Figure 5. Treatment with NVP-AEW541 overcomes resistance to TMZ and induces autophagy in pGBM KNS42 cells. A, cotreatment of pGBM cells with NVP-AEW541 and TMZ resulted in a high degree of synergy in KNS42 cells (CI = 0.61) as calculated by the median-effect analysis. In contrast, SF188 cells showed an antagonistic interaction (CI = 2.16). B, Western blot analysis of LC3 expression in response to NVP-AEW541 treatment of IGF2-stimulated KNS42 cells. An increased conversion of the cytosolic LC3-I to the autophagosome-associated LC3-II form was observed in a time- and concentration (1×, 3×, 5× GI50)-dependent manner. C, electron microscopy of vehicle-treated KNS42 cells. Little vacuolation was observed, with cytoplasm mostly containing multivesicular bodies (arrow). i, original magnification, ×5,000. ii, original magnification, ×25,000. D, treatment of KNS42 cells with NVP-AEW541 at 5× GI50 for 1 hour. Electron micrographs reveal the accumulation of large and small cytoplasmic vacuoles. i, original magnification, ×5,000. ii, vacuoles filled with electron-dense inclusions resembling autolysosomes (arrow). Original magnification, ×20,000. iii, cytoplasm with numerous large empty vacuoles and smaller ones surrounded by double membrane indicative of autophagosomes (arrow). Original magnification, ×20,000. iv, autolysosomes filled with homogeneous digested material (arrow), in some cases fusing together. Original magnification, ×20,000. Figure 5. Treatment with NVP-AEW541 overcomes resistance to TMZ and induces autophagy in pGBM KNS42 cells. A, cotreatment of pGBM cells with NVP-AEW541 and TMZ resulted in a high degree of synergy in KNS42 cells (CI = 0.61) as calculated by the median-effect analysis. In contrast, SF188 cells showed an antagonistic interaction (CI = 2.16). B, Western blot analysis of LC3 expression in response to NVP-AEW541 treatment of IGF2-stimulated KNS42 cells. An increased conversion of the cytosolic LC3-I to the autophagosome-associated LC3-II form was observed in a time- and concentration (1×, 3×, 5× GI50)-dependent manner. C, electron microscopy of vehicle-treated KNS42 cells. Little vacuolation was observed, with cytoplasm mostly containing multivesicular bodies (arrow). i, original magnification, ×5,000. ii, original magnification, ×25,000. D, treatment of KNS42 cells with NVP-AEW541 at 5× GI50 for 1 hour. Electron micrographs reveal the accumulation of large and small cytoplasmic vacuoles. i, original magnification, ×5,000. ii, vacuoles filled with electron-dense inclusions resembling autolysosomes (arrow). Original magnification, ×20,000. iii, cytoplasm with numerous large empty vacuoles and smaller ones surrounded by double membrane indicative of autophagosomes (arrow). Original magnification, ×20,000. iv, autolysosomes filled with homogeneous digested material (arrow), in some cases fusing together. Original magnification, ×20,000. More
Images
Combination of <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> and lapatinib cooperatively inhibits the growth o...
Published: 06 April 2011
Figure 6. Combination of NVP-AEW541 and lapatinib cooperatively inhibits the growth of NVP-AEW541 resistant murine rhabdomyosarcoma primary cell cultures with Igf1r/Her2 complexes. Cell viability assay for naïve, untreated (U20325; A) and NVP-AEW541 innately resistant mouse rhabdomyosarcoma primar... More
Images
<span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> inhibits the growth of mouse tumor primary cell cultures. A, cel...
Published: 06 April 2011
Figure 2. NVP-AEW541 inhibits the growth of mouse tumor primary cell cultures. A, cell viability assay for mouse rhabdomyosarcoma cultures treated with various doses of NVP-AEW541 and immunoblot showing expression levels of Igf1r in mouse rhabdomyosarcoma primary cell cultures (U20325 and U21089) ... More
Images
Investigating the mechanism of <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> resistance in tumors. A, Western ...
Published: 06 April 2011
Figure 5. Investigating the mechanism of NVP-AEW541 resistance in tumors. A, Western blot analysis of tumors from untreated and NVP-AEW541 treated mice. Immunoblotting shows that mice resistant to NVP-AEW541 had stochastically increased expression of Igf1r and Her2 as well as activated Mapk signal... More
Images
<span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> induces tumor growth inhibition, cell cycle arrest, and apoptosi...
Published: 06 April 2011
Figure 3. NVP-AEW541 induces tumor growth inhibition, cell cycle arrest, and apoptosis in primary tumor cell cultures. A, treating the mouse rhabdomyosarcoma primary cell cultures (U20325) with increasing amount of NVP-AEW541 induces cell cycle arrest in the G1 phase. B, at moderately high concentrations of NVP-AEW541, the mouse rhabdomyosarcoma cells (U20325) show increased apoptosis as evident by the presence of cleaved caspase-3 at 5 μmol/L (but not at 2 μmol/L, unpublished data). C, representative (median) images of luminescence emitted by rhabdomyosarcoma primary cell cultures grown on quail CAM and being treated with DMSO, imatinib, and NVP-AEW541. The images are displayed with a minimum–maximum scale of 2 × 106 to 2 × 107 photons/s/cm2/steradian. D, graphical representation of the intensity of bioluminescence signal emitted by rhabdomyosarcoma primary cell cultures grown on quail CAM that were being treated with DMSO, imatinib (100 μmol/L), or NVP-AEW541 (10 μmol/L). Figure 3. NVP-AEW541 induces tumor growth inhibition, cell cycle arrest, and apoptosis in primary tumor cell cultures. A, treating the mouse rhabdomyosarcoma primary cell cultures (U20325) with increasing amount of NVP-AEW541 induces cell cycle arrest in the G1 phase. B, at moderately high concentrations of NVP-AEW541, the mouse rhabdomyosarcoma cells (U20325) show increased apoptosis as evident by the presence of cleaved caspase-3 at 5 μmol/L (but not at 2 μmol/L, unpublished data). C, representative (median) images of luminescence emitted by rhabdomyosarcoma primary cell cultures grown on quail CAM and being treated with DMSO, imatinib, and NVP-AEW541. The images are displayed with a minimum–maximum scale of 2 × 106 to 2 × 107 photons/s/cm2/steradian. D, graphical representation of the intensity of bioluminescence signal emitted by rhabdomyosarcoma primary cell cultures grown on quail CAM that were being treated with DMSO, imatinib (100 μmol/L), or NVP-AEW541 (10 μmol/L). More
Images
Effect of <span class="search-highlight">NVP</span>-<span class="search-highlight">AEW541</span> on rhabdomyosarcoma <em>in vivo.</em> A, mice ...
Published: 06 April 2011
Figure 4. Effect of NVP-AEW541 on rhabdomyosarcoma in vivo. A, mice bearing tumors were treated with 50 mg/kg of NVP-AEW541 every 12 hours by oral gavage. This figure shows tumor bearing mice (n = 8) treated with NVP-AEW541 and representative of the (n = 15) total mice tested. A, mice that were partially sensitive to treatment (overall 3 out of 15 were sensitive). B, mice that responded to treatment initially, but slowly evolved drug resistance (3 out of 15). C, mice that showed innate (rapidly developing) resistance (9 out of 15 mice). Figure 4. Effect of NVP-AEW541 on rhabdomyosarcoma in vivo. A, mice bearing tumors were treated with 50 mg/kg of NVP-AEW541 every 12 hours by oral gavage. This figure shows tumor bearing mice (n = 8) treated with NVP-AEW541 and representative of the (n = 15) total mice tested. A, mice that were partially sensitive to treatment (overall 3 out of 15 were sensitive). B, mice that responded to treatment initially, but slowly evolved drug resistance (3 out of 15). C, mice that showed innate (rapidly developing) resistance (9 out of 15 mice). More
Journal Articles
Mol Cancer Ther (2011) 10 (4): 697–707.
Published: 06 April 2011
...Figure 6. Combination of NVP-AEW541 and lapatinib cooperatively inhibits the growth of NVP-AEW541 resistant murine rhabdomyosarcoma primary cell cultures with Igf1r/Her2 complexes. Cell viability assay for naïve, untreated (U20325; A) and NVP-AEW541 innately resistant mouse rhabdomyosarcoma...
Includes: Supplementary data
Images
Antitumor activity of combined inhibition of IGF1R and PDGFRα in an <italic
Published: 08 August 2011
Figure 7. Antitumor activity of combined inhibition of IGF1R and PDGFRα in an in vivo xenograft tumor model of pGBM. A, combination of NVP-AEW541 and imatinib reduced tumor volume (percentage of day 0) more than either compound alone in the KNS42_A4 subcutaneous xenograft model. **, P < 0.01; *, P < 0.05, Student's t test. B, a reduced final tumor weight was observed for the NVP-AEW541 and imatinib combination compared with control tumors or those treated with either agent alone (P < 0.0863, Student's t test). C, MSD assay for phosphorylated IGF1R. NVP-AEW541 resulted in a significant inhibition of phospho-IGF1R, alone or in combination, in contrast to imatinib alone. D, inhibition of phospho-IRS1 was observed after treatment with NVP-AEW541, and especially imatinib, in KNS42_A4 xenografts. E, phospho-Akt levels showed a greater reduction with the combination of NVP-AEW541 and imatinib than either compound alone. F, treatment with imatinib, alone or in combination, significantly reduced phospho-Erk1/2 levels in contrast to NVP-AEW541 alone. ***, P < 0.001; **, P < 0.01; *, P < 0.05, Student's t test. Figure 7. Antitumor activity of combined inhibition of IGF1R and PDGFRα in an in vivo xenograft tumor model of pGBM. A, combination of NVP-AEW541 and imatinib reduced tumor volume (percentage of day 0) more than either compound alone in the KNS42_A4 subcutaneous xenograft model. **, P < 0.01; *, P < 0.05, Student's t test. B, a reduced final tumor weight was observed for the NVP-AEW541 and imatinib combination compared with control tumors or those treated with either agent alone (P < 0.0863, Student's t test). C, MSD assay for phosphorylated IGF1R. NVP-AEW541 resulted in a significant inhibition of phospho-IGF1R, alone or in combination, in contrast to imatinib alone. D, inhibition of phospho-IRS1 was observed after treatment with NVP-AEW541, and especially imatinib, in KNS42_A4 xenografts. E, phospho-Akt levels showed a greater reduction with the combination of NVP-AEW541 and imatinib than either compound alone. F, treatment with imatinib, alone or in combination, significantly reduced phospho-Erk1/2 levels in contrast to NVP-AEW541 alone. ***, P < 0.001; **, P < 0.01; *, P < 0.05, Student's t test. More
Journal Articles
Series: Author Choice
Mol Cancer Ther (2013) 12 (8): 1526–1536.
Published: 08 August 2013
... measured by the FMCA method correlated strongly with that of various tubulin inhibitors but not with that of the IGF-IR inhibitor NVP-AEW541 ( Fig. 2B and C ). Using computer modeling, we showed that PPP is theoretically able to fit into the colchicine-binding pocket of tubulin ( Fig. 4C ). This is partly...
Includes: Supplementary data