scholarly journals COX-2/sEH dual inhibitor PTUPB suppresses glioblastoma growth by targeting epidermal growth factor receptor and hyaluronan mediated motility receptor

Oncotarget ◽  
2017 ◽  
Vol 8 (50) ◽  
pp. 87353-87363 ◽  
Author(s):  
Junyang Li ◽  
Yali Zhou ◽  
Handong Wang ◽  
Yongyue Gao ◽  
Liwen Li ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Dual Inhibitor ◽  
Epidermal Growth ◽  
Cox 2

Epidermal growth factor receptor transactivation is required for proteinase-activated receptor-2-induced COX-2 expression in intestinal epithelial cells

2012 ◽  
Vol 303 (1) ◽  
pp. G111-G119 ◽  
Author(s):  
Christina L. Hirota ◽  
France Moreau ◽  
Vadim Iablokov ◽  
Michael Dicay ◽  
Bernard Renaux ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Intestinal Epithelial Cells ◽  
Growth Factor Receptor ◽  
Intestinal Epithelial ◽  
Kinase Signaling ◽  
Epidermal Growth ◽  
Cox 2

Proteinase-activated receptor (PAR)2, a G protein-coupled receptor activated by serine proteinases, has been implicated in both intestinal inflammation and epithelial proliferation. Cyclooxygenase (COX)-2 is overexpressed in the gut during inflammation as well as in colon cancer. We hypothesized that PAR2 drives COX-2 expression in intestinal epithelial cells. Treatment of Caco-2 colon cancer cells with the PAR2-activating peptide 2-furoyl-LIGRLO-NH2 (2fLI), but not by its reverse-sequence PAR2-inactive peptide, for 3 h led to an increase in intracellular COX-2 protein expression accompanied by a COX-2-dependent increase in prostaglandin E2 production. 2fLI treatment for 30 min significantly increased metalloproteinase activity in the culture supernatant. Increased epidermal growth factor receptor (EGFR) phosphorylation was observed in cell lysates following 40 min of treatment with 2fLI. The broad-spectrum metalloproteinase inhibitor marimastat inhibited both COX-2 expression and EGFR phosphorylation. The EGFR tyrosine kinase inhibitor PD153035 also abolished 2fLI-induced COX-2 expression. Although PAR2 activation increased ERK MAPK phosphorylation, neither ERK pathway inhibitors nor a p38 MAPK inhibitor affected 2fLI-induced COX-2 expression. However, inhibition of either Src tyrosine kinase signaling by PP2, Rho kinase signaling by Y27632, or phosphatidylinositol 3 (PI3) kinase signaling by LY294002 prevented 2fLI-induced COX-2 expression. Trypsin increased COX-2 expression through PAR2 in Caco-2 cells and in an EGFR-dependent manner in the noncancerous intestinal epithelial cell-6 cell line. In conclusion, PAR2 activation drives COX-2 expression in Caco-2 cells via metalloproteinase-dependent EGFR transactivation and activation of Src, Rho, and PI3 kinase signaling. Our findings provide a mechanism whereby PAR2 can participate in the progression from chronic inflammation to cancer in the intestine.

scholarly journals Lycopene Inhibits Activation of Epidermal Growth Factor Receptor and Expression of Cyclooxygenase-2 in Gastric Cancer Cells

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 2113 ◽  
Author(s):  
Hwana Han ◽  
Joo Weon Lim ◽  
Hyeyoung Kim
Keyword(s):  
Gene Expression ◽  
Gastric Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cancer Cells ◽  
Growth Factor Receptor ◽  
Ags Cells ◽  
Epidermal Growth ◽  
Cox 2

Reactive oxygen species (ROS) contribute to the oncogenic phenotype of cancer cells by acting as signaling molecules for inducing proliferation. ROS are known to activate the epidermal growth factor receptor (EGFR), which causes the activation of the Ras/mitogen-activated protein kinases (MAPKs) pathway. The Ras-dependent pathway promotes the activation of nuclear factor-kappa-light-chain-enhancer of activated B cells (NF-κB), a transcriptional modulator of cyclooxygenase-2 (COX-2) that induces cell proliferation. Lycopene is a potent antioxidant carotenoid and is responsible for the red color of fruits and vegetables. This study aims to investigate whether lycopene inhibits proliferation and induces apoptosis in gastric cancer AGS cells by suppressing the EGFR/Ras/MAPK and NF-κB-COX-2 signaling axis. Lycopene decreased cell viability and increased apoptotic indices (DNA fragmentation, apoptosis inducing factor, cleavage of caspase-3 and caspase-9, Bax/Bcl-2 ratio). Lycopene reduced the level of intracellular and mitochondrial ROS and decreased the activation of the ROS-mediated EGFR/Ras/extracellular signal-regulated kinase (ERK) and p38 MAPK pathways, thus leading to attenuation of the DNA-binding activity of NF-κB p50/p50 and the level of COX-2 gene expression. These results show that lycopene-induced apoptosis and inhibition of proliferation occur via inhibition of ROS-activated EGFR/Ras/ERK and p38 MAPK pathways and NF-κB-mediated COX-2 gene expression in AGS cells. In conclusion, consumption of lycopene-enriched foods could decrease the incidence of gastric cancer.

Phase IIb/III double-blind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1–2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX- Lung1): A preliminary report

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8062-8062
Author(s):  
C. Yang ◽  
V. Hirsh ◽  
J. Cadranel ◽  
Y. Chen ◽  
K. Park ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Randomized Trial ◽  
Clinical Benefit ◽  
Growth Factor Receptor ◽  
Dual Inhibitor ◽  
Secondary Resistance ◽  
Bibw 2992 ◽  
Epidermal Growth

8062 Background: No approved therapy exists for NSCLC patients (pts) who have failed chemotherapy (CT) and the reversible epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs), erlotinib (E) or gefitinib (G). The efficacy of BIBW 2992 (Tovok), a potent, irreversible inhibitor of EGFR and human epidermal growth factor receptor 2 (HER2) with preclinical activity against the secondary resistance mutation T790M, in pts progressing after initial clinical benefit on E/G is being assessed in this randomized trial. Methods: Pts with advanced adenocarcinoma of the lung (Stage IIIB/IV; ECOG 0–2), who have failed one or two lines of CT (including platinum) and progressed following at least 12 weeks of E or G are randomized in a 2:1 ratio to receive BSC plus either oral BIBW 2992 50 mg qd or placebo until disease progression or unacceptable toxicity. Primary endpoint is overall survival, with progression-free survival, objective response and clinical benefit rate and duration, safety and quality of life being secondary endpoints. Enrollment of 400 pts is planned (HR=0.70, 85% power). An unblinded interim analysis of tumor response and safety by the independent Data Monitoring Committee (DMC) after the first 40 evaluable pts treated with BIBW 2992 will determine continuation to full accrual. Results: From May to November 2008, 145 pts have been randomized and 76 are still on treatment. Demographics (n=145): median age 59 (range: 30–82); female 68%, current/ex-smokers 38%; metastatic disease 91%, ECOG 0–1 92%; Asian origin 68%. 50% had one prior line of CT. Main prior EGFR-TKI was G in Asians (70%) and E in non-Asians (85%). 40% of pts had achieved a PR or CR on previous treatment with E/G. Duration of prior E/G treatment was >24 weeks and >48 weeks in 80% and 40% of pts, respectively. As expected, diarrhea, rash, anorexia, stomatitis, paronychia, nausea and vomiting were the most frequently observed adverse events. Conclusions: The trial is continuing recruitment after DMC review of efficacy and safety and updated demographics and blinded safety data will be reported. [Table: see text]

Cyclooxygenase-2 and Epidermal Growth Factor Receptor: Pharmacologic Targets for Chemoprevention

2005 ◽  
Vol 23 (2) ◽  
pp. 254-266 ◽  
Author(s):  
Andrew J. Dannenberg ◽  
Scott M. Lippman ◽  
Jason R. Mann ◽  
Kotha Subbaramaiah ◽  
Raymond N. DuBois
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Research Evidence ◽  
Growth Factor Receptor ◽  
Cancer Chemoprevention ◽  
Cyclooxygenase 2 ◽  
Natural Substances ◽  
Epidermal Growth ◽  
Cox 2

Understanding the mechanisms underlying carcinogenesis provides insights that are necessary for the development of therapeutic strategies to prevent cancer. Chemoprevention, the use of drugs or natural substances to inhibit carcinogenesis, is a rapidly evolving aspect of cancer research. Evidence is presented that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are potential pharmacologic targets to prevent cancer. In this paper, we review key data implicating a causal relationship between COX-2, EGFR, and carcinogenesis and possible mechanisms of action. We discuss evidence of crosstalk between COX-2 and EGFR in order to strengthen the rationale for combination chemoprevention, and review plans for a clinical trial that will evaluate the concept of combination chemoprevention targeting COX-2 and EGFR.

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