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PURPOSE: This study investigates the role and effectiveness of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in oral cancer, focusing on the clinical relevance of EGFR and myeloid cell leukemia-1 (Mcl-1) in head and neck cancers (HNCs). It aims to explore the molecular mechanism of afatinib, a TKI, in treating human oral cancer. METHODS: We conducted an in silico analysis using databases like The Cancer Genome Atlas, Gene Expression Omnibus, and Clinical Proteomic Tumor Analysis Consortium, along with immunohistochemistry staining, to study EGFR and Mcl-1 expression in HNCs. For investigating afatinib's anticancer properties, we performed various in vitro and in vivo analyses, including trypan blue exclusion assay, Western blotting, 4'-6-diamidino-2-phenylindole staining, flow cytometry, quantitative real-time PCR, Mitochondrial membrane potential assay, overexpression vector construction, transient transfection, and a tumor xenograft model. RESULTS: Higher expression levels of EGFR and Mcl-1 were observed in HNC patient tissues compared to normal tissues, with their co-expression significantly linked to poor prognosis. There was a strong correlation between EGFR and Mcl-1 expressions in oral cancer patients. Afatinib treatment induced apoptosis and suppressed Mcl-1 in oral cancer cell lines without the EGFR T790M mutation. The mechanism of afatinib-induced apoptosis involved the EGFR/mTOR/Mcl-1 axis, as shown by the effects of mTOR activator MHY1485 and inhibitor rapamycin. Afatinib also increased Bim expression, mitochondrial membrane permeabilization, and cytochrome c release. It significantly lowered tumor volume without affecting body, liver, and kidney weights. CONCLUSION: Afatinib, targeting the EGFR/mTOR/Mcl-1 axis, shows promise as a therapeutic strategy for oral cancer, especially in patients with high EGFR and Mcl-1 expressions.
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The rhizome of Zingiber officinale (Z. officinale), commonly known as ginger, has been characterized as a potential drug candidate due to its antitumor effects. However, the chemotherapeutic effect of ginger on human oral cancer remains poorly understood. In this study, we examined the effects of an ethanol extract of Z. officinale rhizomes (ZOE) on oral cancer and identified the components responsible for its pharmacological activity. ZOE exerts its inhibitory activity in oral cancer by inducing both autophagy and apoptosis simultaneously. Mechanistically, ZOE-induced autophagy and apoptosis in oral cancer are attributed to the reactive oxygen species (ROS)-mediated endoplasmic reticulum stress response. Additionally, we identified two active components of ZOE, 1-dehydro-6-gingerdione and 8-shogaol, which were sufficient to stimulate autophagy initiation and apoptosis induction by enhancing CHOP expression. These results suggest that ZOE and its two active components induce ROS generation, upregulate CHOP, initiate autophagy and apoptosis, and hold promising therapeutics against human oral cancer.
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Apoptosis , Autofagia , Estrés del Retículo Endoplásmico , Neoplasias de la Boca , Extractos Vegetales , Especies Reactivas de Oxígeno , Factor de Transcripción CHOP , Zingiber officinale , Zingiber officinale/química , Humanos , Autofagia/efectos de los fármacos , Apoptosis/efectos de los fármacos , Factor de Transcripción CHOP/metabolismo , Neoplasias de la Boca/tratamiento farmacológico , Neoplasias de la Boca/patología , Neoplasias de la Boca/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Extractos Vegetales/farmacología , Línea Celular Tumoral , Estrés del Retículo Endoplásmico/efectos de los fármacos , Animales , Catecoles/farmacología , Ratones , Rizoma/química , Ensayos Antitumor por Modelo de Xenoinjerto , Antineoplásicos Fitogénicos/farmacologíaRESUMEN
OBJECTIVE: Pseudolaric acid B (PAB) is a novel diterpenoid derived from the traditional Chinese medicinal herb Cortex pseudolaricis that exerts anticancer, anti-inflammatory, and immunomodulatory properties. While the anticancer potential of PAB has been studied, its effects on metastasis have not been well-studied. This study aims to determine the inhibitory effects of PAB on HSC-3 human tongue squamous cell carcinoma (TSCC) cell line. DESIGN: Cell viability and soft agar colony formation assays were conducted to assess cellular proliferation and in vitro tumorigenic capacity of TSCC cells, respectively. Additionally, wound healing, transwell migration, and invasion assays were conducted to monitor the aggressive behavior of TSCC cells. Furthermore, Western blotting analysis was conducted to reveal the signaling pathways involved in the modulation of epithelial-mesenchymal transition (EMT). RESULTS: The migratory and invasive capacities of HSC-3 cells were suppressed by PAB irrespective of their proliferation states. PAB's effects on EMT involved upregulation of E-cadherin expression and downregulation of Twist; these were concomitantly accompanied by downregulated phosphorylation of epidermal growth factor receptor (EGFR). CONCLUSIONS: PAB suppresses human TSCC in vitro by regulating Twist/E-cadherin through the EGFR signaling pathway. PAB may have potential as a candidate antimetastatic drug for TSCC treatment.
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Carcinoma de Células Escamosas , Diterpenos , Neoplasias de la Lengua , Humanos , Neoplasias de la Lengua/genética , Carcinoma de Células Escamosas/genética , Línea Celular Tumoral , Diterpenos/farmacología , Proliferación Celular , Lengua/patología , Receptores ErbB/metabolismo , Cadherinas/metabolismo , Movimiento Celular , Regulación Neoplásica de la Expresión GénicaRESUMEN
Hypopharyngeal squamous cell carcinoma (HSCC) is a relatively rare form of head and neck cancer that is notorious for its poor prognosis and low overall survival rate. This highlights the need for new therapeutic options for this malignancy. The objective of the present study was to examine the ability of caffeic acid phenethyl ester (CAPE), which is an active compound found in propolis, to combat HSCC tumor growth. CAPE exerted its tumorsuppressive activity in HSCC cell lines through the induction of apoptosis. Mechanistically, the CAPEmediated apoptotic process was attributed to the perturbation of the mitochondrial membrane potential and the activation of caspase9. CAPE also modulated survivin and Xlinked inhibitor of apoptosis, which are potent members of the inhibitors of apoptosis protein family, either through transcriptional or posttranslational regulation, leading to HSCC cell line death. Therefore, the findings of the present study suggested that CAPE is an effective treatment alternative for HSCC via the stimulation of mitochondriadependent apoptosis.