scholarly journals Deguelin Induces Apoptosis by Targeting Both EGFR-Akt and IGF1R-Akt Pathways in Head and Neck Squamous Cell Cancer Cell Lines

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Yuh Baba ◽  
Masato Fujii ◽  
Toyonobu Maeda ◽  
Atsuko Suzuki ◽  
Satoshi Yuzawa ◽  
...  
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Cell Lines ◽  
Squamous Cell ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Annexin V ◽  
Akt Activation ◽  
Igf1r Signaling ◽  
Induced Apoptosis

Deguelin, a rotenoid compound from the African plantMundulea sericea(Leguminosae), has been shown to possess antitumor activities but the exact role for the growth factor receptor mediated signaling pathway in head and neck squamous cell carcinoma (HNSCC) is currently still unclear. In the present study, we investigated the effect of deguelin on epidermal growth factor receptor (EGFR) and insulin-like growth factor-1 receptor (IGF1R) pathways in HNSCC cell lines. Flowcytometric analysis revealed accumulation of annexin V positivity in deguelin-treated cells, showing that deguelin induced apoptosis. The deguelin-induced apoptosis was accompanied by the reduction of constitutive phosphorylated levels of IGF1R, Akt, and extracellular signal-regulated kinase1/2 (ERK1/2). LY294002-mediated inhibition of phosphatidylinositol-3 kinase, which is an upstream effector for Akt activation, increased cleavage of poly(ADP-ribosyl) polymerase (PARP) but ERK inhibition by U0126 did not. Deguelin inhibited both IGF-1- and EGF-induced Akt activation. These results showed that deguelin possessed antitumor effect by targeting Akt in dual axis such as EGFR and IGF1R signaling pathways and suggested that it provides an applicable therapeutic strategy for HNSCC patients.

scholarly journals mTOR/EGFR/iNOS/MAP2K1/FGFR/TGFB1 Are Druggable Candidates for N-(2,4-Difluorophenyl)-2′,4′-Difluoro-4-Hydroxybiphenyl-3-Carboxamide (NSC765598), With Consequent Anticancer Implications

2021 ◽  
Vol 11 ◽  
Author(s):  
Bashir Lawal ◽  
Ching-Yu Lee ◽  
Ntlotlang Mokgautsi ◽  
Maryam Rachmawati Sumitra ◽  
Harshita Khedkar ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Squamous Cell ◽  
Protein Interactions ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Growth Factor Receptor ◽  
Anticancer Activities

BackgroundThe application of computational and multi-omics approaches has aided our understanding of carcinogenesis and the development of therapeutic strategies. NSC765598 is a novel small molecule derivative of salicylanilide. This study aims to investigate the ligand-protein interactions of NSC765598 with its potential targets and to evaluate its anticancer activities in vitro.MethodsWe used multi-computational tools and clinical databases, respectively, to identify the potential drug target for NSC765598 and analyze the genetic profile and prognostic relevance of the targets in multiple cancers. We evaluated the in vitro anticancer activities against the National Cancer Institute 60 (NCI60) human tumor cell lines and used molecular docking to study the ligand-protein interactions. Finally, we used the DTP-COMPARE algorithm to compare the NSC765598 anticancer fingerprints with NCI standard agents.ResultsWe identified mammalian target of rapamycin (mTOR)/epidermal growth factor receptor (EGFR)/inducible nitric oxide synthase (iNOS)/mitogen-activated protein 2 kinase 1 (MAP2K1)/fibroblast growth factor receptor (FGFR)/transforming growth factor-β1 (TGFB1) as potential targets for NSC765598. The targets were enriched in cancer-associated pathways, were overexpressed and were of prognostic relevance in multiple cancers. Among the identified targets, genetic alterations occurred most frequently in EGFR (7%), particularly in glioblastoma, esophageal squamous cell cancer, head and neck squamous cell cancer, and non–small-cell lung cancer, and were associated with poor prognoses and survival of patients, while other targets were less frequently altered. NSC765598 displayed selective antiproliferative and cytotoxic preferences for NSCLC (50% growth inhibition (GI50) = 1.12–3.95 µM; total growth inhibition (TGI) = 3.72–16.60 μM), leukemia (GI50 = 1.20–3.10 µM; TGI = 3.90–12.70 μM), melanoma (GI50 = 1.45–3.59 µM), and renal cancer (GI50 = 1.38–3.40 µM; TGI = 4.84–13.70 μM) cell lines, while panels of colon, breast, ovarian, prostate, and central nervous system (CNS) cancer cell lines were less sensitive to NSC765598. Interestingly, NSC765598 docked well into the binding cavity of the targets by conventional H-bonds, van der Waal forces, and a variety of π-interactions, with higher preferences for EGFR (ΔG = −11.0 kcal/mol), NOS2 (ΔG = −11.0 kcal/mol), and mTOR (ΔG = −8.8 kcal/mol). NSC765598 shares similar anti-cancer fingerprints with NCI standard agents displayed acceptable physicochemical values and met the criteria of drug-likeness.ConclusionNSC765598 displayed significant anticancer and potential multi-target properties, thus serve as a novel candidate worthy of further preclinical studies.

scholarly journals Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 795 ◽  
Author(s):  
Sylvie Job ◽  
Aurélien de Reyniès ◽  
Betty Heller ◽  
Amélie Weiss ◽  
Eric Guérin ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Cell Lines ◽  
Squamous Cell ◽  
Growth Factor Receptor ◽  
Epidermal Growth

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/extracellular signal–regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)]. Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.

scholarly journals Cisplatin-Based Chemotherapy Options for Recurrent and/or Metastatic Squamous Cell Cancer of the Head and Neck

2013 ◽  
Vol 5 ◽  
pp. CMT.S10409 ◽  
Author(s):  
Kelsey P. Pendleton ◽  
Jennifer R. Grandis
Keyword(s):  
Growth Factor ◽  
Head And Neck ◽  
Squamous Cell ◽  
Excision Repair ◽  
Cell Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Growth Factor Receptor ◽  
Treatment Regimens ◽  
First Line Therapy ◽  
Phosphoinositide 3 Kinase

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. Treatment is limited to chemotherapeutic approaches. Cisplatin is an established and effective treatment for R/M HNSCC, and many studies have investigated cisplatin treatment in combination with other agents. Even when being treated with first line therapy (cisplatin + 5-fluorouracil + cetuximab), overall survival is only 10 months, indicating the need for novel chemotherapeutics and treatment regimens. Current research is focused on molecular targeting therapies inhibiting epidermal growth factor receptor, phosphoinositide-3-kinase/Akt/mammalian target of rapamycin, and vascular endothelial growth factor pathways. A variety of clinical trials have been completed and are currently underway with encouraging results. Finally, future directions of cisplatin-based R/M HNSCC treatment may include targeting specific pathways known to induce cisplatin resistance, such as nucleotide excision repair and inhibition of apoptosis, in hopes to enhance response to cisplatin therapy.

Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Expression in Squamous Cell Carcinomas of the Head and Neck

2001 ◽  
Vol 111 (10) ◽  
pp. 1834-1841 ◽  
Author(s):  
Csilla Neuchrist ◽  
Boban M. Erovic ◽  
Alessandra Handisurya ◽  
Georg E. Steiner ◽  
Patricia Rockwell ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Head And Neck ◽  
Squamous Cell ◽  
Growth Factor Receptor ◽  
Squamous Cell Carcinomas ◽  
Vascular Endothelial ◽  
Endothelial Growth Factor
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