scholarly journals Lapatinib, a Dual Inhibitor of Epidermal Growth Factor Receptor (EGFR) and HER-2, Enhances Radiosensitivity in Mouse Bladder Tumor Line-2 (MBT-2) Cells In Vitro and In Vivo

2018 ◽  
Vol 24 ◽  
pp. 5811-5819 ◽  
Author(s):  
Yi Mu ◽  
Deyu Sun
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Bladder Tumor ◽  
Growth Factor Receptor ◽  
Tumor Line ◽  
Dual Inhibitor ◽  
Her 2 ◽  
Epidermal Growth

scholarly journals Disruption of TP63-miR-27a* Feedback Loop by Mutant TP53 in Head and Neck Cancer

2019 ◽  
Vol 112 (3) ◽  
pp. 266-277 ◽  
Author(s):  
Nikhil S Chari ◽  
Cristina Ivan ◽  
Xiandong Le ◽  
Jinzhong Li ◽  
Ainiwaer Mijiti ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Oral Cavity ◽  
Head And Neck ◽  
Feedback Loop ◽  
Growth Factor Receptor ◽  
Epidermal Growth

Abstract Background Alterations in the epidermal growth factor receptor and PI3K pathways in head and neck squamous cell carcinomas (HNSCCs) are frequent events that promote tumor progression. Ectopic expression of the epidermal growth factor receptor–targeting microRNA (miR), miR-27a* (miR-27a-5p), inhibits tumor growth. We sought to identify mechanisms mediating repression of miR-27a* in HNSCC, which have not been previously identified. Methods We quantified miR-27a* in 47 oral cavity squamous cell carcinoma patient samples along with analysis of miR-27a* in 73 oropharyngeal and 66 human papillomavirus–positive (HPV+) samples from The Cancer Genome Atlas. In vivo and in vitro TP53 models engineered to express mutant TP53, along with promoter analysis using chromatin immunoprecipitation and luciferase assays, were used to identify the role of TP53 and TP63 in miR-27a* transcription. An HNSCC cell line engineered to conditionally express miR-27a* was used in vitro to determine effects of miR-27a* on target genes and tumor cells. Results miR-27a* expression was repressed in 47 oral cavity tumor samples vs matched normal tissue (mean log2 difference = −0.023, 95% confidence interval = −0.044 to −0.002; two-sided paired t test, P = .03), and low miR-27a* levels were associated with poor survival in HPV+ and oropharyngeal HNSCC samples. Binding of ΔNp63α to the promoter led to an upregulation of miR-27a*. In vitro and in vivo findings showed that mutant TP53 represses the miR-27a* promoter, downregulating miR-27a* levels. ΔNp63α and nucleoporin 62, a protein involved in ΔNP63α transport, were validated as novel targets of miR-27a*. Conclusion Our results characterize a negative feedback loop between TP63 and miR-27a*. Genetic alterations in TP53, a frequent event in HNSCC, disrupt this regulatory loop by repressing miR-27a* expression, promoting tumor survival.

scholarly journals An endosomally localized isoform of Eps15 interacts with Hrs to mediate degradation of epidermal growth factor receptor

2008 ◽  
Vol 180 (6) ◽  
pp. 1205-1218 ◽  
Author(s):  
Ingrid Roxrud ◽  
Camilla Raiborg ◽  
Nina Marie Pedersen ◽  
Espen Stang ◽  
Harald Stenmark
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Adaptor Protein ◽  
Coated Pits ◽  
Kinase Substrate ◽  
Epidermal Growth

Down-regulation of activated and ubiquitinated growth factor (GF) receptors by endocytosis and subsequent lysosomal degradation ensures attenuation of GF signaling. The ubiquitin-binding adaptor protein Eps15 (epidermal growth factor receptor [EGFR] pathway substrate 15) functions in endocytosis of such receptors. Here, we identify an Eps15 isoform, Eps15b, and demonstrate its expression in human cells and conservation across vertebrate species. Although both Eps15 and Eps15b interact with the endosomal sorting protein Hrs (hepatocyte growth factor–regulated tyrosine kinase substrate) in vitro, we find that Hrs specifically binds Eps15b in vivo (whereas adaptor protein 2 preferentially interacts with Eps15). Although Eps15 mainly localizes to clathrin-coated pits at the plasma membrane, Eps15b localizes to Hrs-positive microdomains on endosomes. Eps15b overexpression, similarly to Hrs overexpression, inhibits ligand-mediated degradation of EGFR, whereas Eps15 is without effect. Similarly, depletion of Eps15b but not Eps15 delays degradation and promotes recycling of EGFR. These results indicate that Eps15b is an endosomally localized isoform of Eps15 that is present in the Hrs complex via direct Hrs interaction and important for the sorting function of this complex.

scholarly journals Quantifying the effects of combination trastuzumab and radiation therapy in human epidermal growth factor receptor 2 positive breast cancer

2020 ◽  
Author(s):  
Meghan J Bloom ◽  
Patrick N Song ◽  
John Virostko ◽  
Thomas E Yankeelov ◽  
Anna G Sorace
Keyword(s):  
Cell Proliferation ◽  
Epidermal Growth Factor Receptor ◽  
Radiation Therapy ◽  
Growth Factor ◽  
Combination Treatment ◽  
Growth Factor Receptor ◽  
Additive Effects ◽  
Epidermal Growth

Abstract Background: Trastuzumab, a clinical antibody targeted to the human epidermal growth factor receptor 2 (HER2), has been shown to sensitize cells to radiation in vitro. Current studies lack longitudinal evaluation of cellular response and in vivo data is limited. The purpose of this study is to quantify the effects of combination trastuzumab and radiation therapy in vitro and in vivo over time to determine if there is a synergistic interaction. Methods: EGFP expressing BT474, SKBR3 and MDA-MB-231 cell lines were treated with 0.1 ng/ml of trastuzumab, 5 or 10 Gy of radiation, or combination treatment, and imaged using fluorescence live cell microscopy for one week. The Bliss independence model was used to quantify the effects of combination treatment. HER2+ tumor bearing mice (female NU/J) (N=34) were treated with saline, 10 mg/kg of trastuzumab, 5 or 10 Gy of radiation, or combination treatment. Tumor size was measured three times per week for four weeks via caliper measurements. Additional mice (N=13) were treated with 10 mg/kg of trastuzumab, 5 Gy of radiation, or combination treatment. Tumors were harvested at one week and evaluated with immunohistochemistry for inflammation (CD45), vascularity (CD31 and α-SMA), and hypoxia (pimonidazole). Results: Altering the order of therapies did not significantly affect BT474 cell proliferation in vitro (P>0.05). The interaction index calculations revealed additive effects of trastuzumab and radiation treatment in all three cell lines in vitro. In vivo results revealed significant differences in tumor response between mice treated with 5 and 10 Gy single agent radiation (P < 0.001); however, no difference was seen in the combination groups when trastuzumab was added to the radiation regimen (P=0.56), indicating a lower dose of radiation could be used without decreasing therapeutic efficacy. Histology results revealed increases in inflammation (CD45+) in mice receiving trastuzumab (P<0.05). Conclusions: Longitudinal evaluation of cell proliferation in vitro showed additive effects of combination therapy. In vivo results show a potential to achieve the same efficacy of treatment with reduced radiation when also administering trastuzumab. Further evaluation of tumor microenvironmental alterations during treatment could identify mechanisms of increased therapeutic efficacy in this regimen.

Antibody-nanoparticle conjugate constructed with trastuzumab and nab-paclitaxel for the targeted therapy of positive human epidermal growth factor receptor 2 gastric cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15506-e15506
Author(s):  
Jian Xiong ◽  
Haijun Zhang
Keyword(s):  
Gastric Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tumor Volume ◽  
Growth Factor Receptor ◽  
Epidermal Growth

e15506 Background: Gastric cancer is the most lethal malignancies in the digestive system. This study was to investigate antibody-nanoparticle conjugate (ANC) constructed with Herceptin® and Abraxane® (Herceptin®/Abraxane®) as a novel strategy of targeted therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer. Methods: Firstly, we fabricated the ANC with Herceptin and Abraxane by a “one-step” synthesis using EDC/NHS. In vitro study, the cell viability, apoptosis and cell cycle of the positive HER2 gastric cancer NCI-N87 cells were measured and compared in four groups of PBS, paclitaxel (Taxol), nano- paclitaxel (Abraxane) and ANC (Herceptin/ Abraxane). In addition, we constructed gastric cancer xenograft model in nude mice to evaluate the targeted antitumor effect in vivo. Furthermore, we chose the NIR797 to locate on the ANC and use the NIR imaging to demonstrate that the ANC could more precise target and delayed release of paclitaxel. Results: ANC of Herceptin/Abraxane was spherical in shape and in a suitable size (289.18 nm±102.6 nm). In vitro, the half-maximal inhibitory concentration (IC50), defined as the concentration of Taxol equivalent needed to kill 50% of cells, was found to be 0.24, 0.13 and 0.048 μg/ml for Taxol , Abraxane and ANC of Herceptin/Abraxane respectively for NCI-N87 cells with an excellent dose-effect relationship. Compared with Taxol and Abraxane, ANC of Herceptin/Abraxane could induce significant G2/M arrest. In vivo, at 4 weeks after treatment, mice treated by ANC of Herceptin/Abraxane had a mean tumor volume of 233±24 mm3, Abraxane of 559±97 mm3, Taxol of 871±94 mm3 and PBS as control of 1576±190 mm3. Obviously, the ANC could surpasses Abraxane and Taxol in reducing tumor volume with lesser side effects. Furthermore, NIRF imaging indicated a better targeting and sustained release of paclitaxel with ANC than that with Abraxane and Taxol. Conclusions: Antibody-nanoparticle conjugate of Herceptin/Abraxane could mediate targeted therapy and enhance antitumor activity, which could represent a novel targeted therapeutic agent for positive HER2 gastric cancer.

Σχεδιασμός, σύνθεση και φαρμακολογική αξιολόγηση νέων υποκατεστημένων ισοστερών πουρίνης

2018 ◽  
Author(s):  
Ευθύμιος-Σπυρίδων Γαβριήλ
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
In Silico ◽  
Growth Factor Receptor ◽  
Her 2 ◽  
Epidermal Growth

Οι Πουρίνες διαθέτουν τεράστια βιολογική σημασία, καθώς αποτελούν δομικά συστατικά του γενετικού υλικού και μορίων που συμμετέχουν σε μεταβολικές οδούς και σηματοδοτικούς μηχανισμούς εντός και εκτός του κυττάρου. Για το λόγο αυτό, τα Πουρινικά ανάλογα ή ισοστερή, ενώσεις δηλαδή που προσομοιάζουν τα φυσιολογικά Πουρινικά παράγωγα, μπορούν να χρησιμοποιηθούν στην αντιμετώπιση μιας πληθώρας νόσων στοχεύοντας συγκεκριμένες κυτταρικές διεργασίες που σχετίζονται με την παθογένεσή τους. Η προσέγγιση αυτή έχει αποδεδειγμένη επιτυχία, όπως φαίνεται από τα διάφορα φάρμακα αυτής της κατηγορίας που έχουν λάβει έγκριση τις τελευταίες δεκαετίες. Στα πλαίσια της προσπάθειας αυτής, πορεύεται και η συγκεκριμένη διατριβή, καθώς αντικείμενό της είναι ο Σχεδιασμός, η Σύνθεση και η Φαρμακολογική αξιολόγηση νέων υποκατεστημένων ισοστερών Πουρίνης ως πιθανών αντικαρκινικών παραγόντων.Το περιεχόμενο της διατριβής διακρίνεται σε τρία μέρη, τα οποία περιγράφονται αναλυτικά στα Κεφάλαια 1, 2 και 3. Στο πρώτο μέρος, χρησιμοποιώντας ως οδηγό ενώσεις που είχαν συντεθεί παλαιότερα στο εργαστήριο και είχαν εμφανίσει αξιόλογη δράση σε διάφορες καρκινικές σειρές, σχεδιάστηκαν και συντέθηκαν νέα υποκατεστημένα παράγωγα πυραζολο[3,4-c]πυριδίνης, τα οποία αξιολογήθηκαν φαρμακολογικά ενάντια σε καρκινικές σειρές μελανώματος A2058 και προστάτη DU145 και PC3, ενώ πραγματοποιήθηκε περαιτέρω μελέτη των πιο δραστικών παραγώγων επί της δράσης τους στον κυτταρικό κύκλο. Στο δεύτερο μέρος, σχεδιάστηκαν και συντέθηκαν νέα υποκατεστημένα ισοστερή Πουρίνης, που ανήκουν σε τρία διαφορετικά ετεροκυκλικά συστήματα, ως πιθανοί αναστολείς του Υποδοχέα του Επιδερμικού Αυξητικού Παράγοντα (Epidermal Growth Factor Receptor, EGFR). Η ένωση-οδηγός που χρησιμοποιήθηκε ήταν το Lapatinib (Tykerb®), εγκεκριμένο φάρμακο, που αναστέλλει τόσο το συγκεκριμένο υποδοχέα όσο και τον HER-2, ένα ακόμα σημαντικό μέλος αυτής της οικογένειας υποδοχέων. Τα νέα μόρια-στόχοι αξιολογήθηκαν ως αναστολείς της φωσφορυλίωσης του υποδοχέα σε κυτταρικό επίπεδο, για την απευθείας ανασταλτική τους δράση επί του ενδοκυτταρικού τμήματος κινάσης του υποδοχέα, καθώς και για την κυτταροτοξικότητά τους στις κυτταρικές σειρές μη μικροκυτταρικού καρκίνου πνεύμονα Α549 και καρκίνου του μαστού HCC1954, που σχετίζονται με υπερέκφραση των υποδοχέων EGFR-WT και HER-2 αντίστοιχα. Στα πιο δραστικά παράγωγα έγινε περαιτέρω μελέτη των επιπέδων κυτταρικής πρόσληψης και των in vivo φαρμακοκινητικών ιδιοτήτων τους.Tο τρίτο μέρος περιλαμβάνει το σχεδιασμό και τη σύνθεση νέων πυραζολοπυριδινών και πυρρολοπυριδινών, ως πιθανών αναστολέων της μεταλλαγμένης κινάσης B-RafV600E, η οποία απαντάται περίπου στο 50% των περιπτώσεων μελανώματος. Ως ένωση-οδηγός χρησιμοποιήθηκε το Vemurafenib (Zelboraf®), εγκεκριμένο φάρμακο που αναστέλλει το συγκεκριμένο ένζυμο και εμφανίζει εντυπωσιακά θεραπευτικά αποτελέσματα. Τα νέα μόρια-στόχοι ανήκουν σε τέσσερα διαφορετικά ετεροκυκλικά συστήματα και κατά την περίοδο συγγραφής της παρούσας διατριβής, η φαρμακολογική τους αξιολόγηση βρισκόταν ακόμα σε εξέλιξη.Στο τελευταίο μέρος πραγματοποιείται μία σύνοψη-ανασκόπηση των αποτελεσμάτων των επιμέρους εργασιών και περιγράφονται οι μελλοντικοί στόχοι, που αφορούν, πρώτον, την αξιοποίηση των σχέσεων δομής-δράσης που εξήχθησαν σε κάθε θέμα, προκειμένου σε συνδυασμό με την in silico μελέτη της πρόσδεσης των μορίων στο στόχο, να σχεδιαστεί η επόμενη γενιά παραγώγων και δεύτερον, την in vivo φαρμακολογική αξιολόγηση των δραστικότερων ενώσεων.

scholarly journals Epidermal growth factor receptor regulates pancreatic fibrosis

2009 ◽  
Vol 297 (3) ◽  
pp. G434-G441 ◽  
Author(s):  
Stacy A. Blaine ◽  
Kevin C. Ray ◽  
Kevin M. Branch ◽  
Pamela S. Robinson ◽  
Robert H. Whitehead ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Pancreatic Fibrosis ◽  
Pancreatic Stellate Cells ◽  
Heparin Binding ◽  
Epidermal Growth

The development of pancreatic fibrosis has been shown to be a major component in several diseases of the pancreas including pancreatic cancer, chronic pancreatitis, and type 2 diabetes mellitus, but its actual role in the progression of these disorders is still unknown. This fibrosis is characterized by stromal expansion and the excessive deposition of extracellular matrix (ECM) that replaces pancreatic tissue. This eventually leads to dysregulation of ECM turnover, production of cytokines, restriction of blood flow, and often exocrine and endocrine insufficiencies. Activated pancreatic stellate cells (PSCs) have been identified as key mediators in the progression of pancreatic fibrosis, serving as the predominant source of excess ECM proteins. Previously, we found that overexpression of the growth factor heparin-binding epidermal growth factor-like growth factor (HB-EGF) in pancreatic islets led to intraislet fibrosis. HB-EGF binds to and activates two receptors, epidermal growth factor receptor (EGFR) and ErbB4, as well as heparin moieties and CD9/DRAP27. To understand the mechanism underlying the induction of fibrogenesis by HB-EGF, we utilized a hypomorphic allele of Egfr, the Waved-2 allele, to demonstrate that EGFR signaling regulates fibrogenesis in vivo. Using an in vitro cell migration assay, we show that HB-EGF regulates both chemoattraction and stimulation of proliferation of PSCs via EGFR activation.

Sign in / Sign up

Export Citation Format

Share Document