Suppressive function of low‐dose deguelin on the invasion of oral cancer cells by downregulating tumor necrosis factor alpha–induced nuclear factor‐kappa B signaling

Liu, Yu Peng; Lee, J.; Lai, Tsung‐Ching; Lee, Chien Hsin; Hsiao, Ya Wen; Chen, Po Shen; Liu, Wei Ting; Hong, Chi Yuan; Lin, Se Kwan; Kuo, Mark Yen‐Ping; Lu, Pei Jung; Hsiao, Michael

doi:10.1002/hed.24034

Cited by 25 publications

(21 citation statements)

References 42 publications

(82 reference statements)

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“…Here, we demonstrated that deguelin has a combination effect with AG1478 in PIK3CA mutant HNSCC cells. Previously, deguelin alone was reported to induce apoptosis via AKT signaling inhibition, autophagy, and CDK4/Survivin degradation at high doses (50 or 100 μM) [20] and to suppress invasive ability at a low dose (0.1 μM) in HNSCC cells [23]. Although deguelin was reported to sensitize HNSCC cells to 5-fluorouracil (FU) [20], to the best of our knowledge, this is the first report that deguelin has a combination effect with an EGFR TKI for induction of apoptosis in HNSCC cells.…”

Section: Discussionmentioning

confidence: 99%

Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

Baba

Maeda

Suzuki

et al. 2017

IJMS

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Head and neck squamous cell carcinoma (HNSCC) is known to be intrinsically resistant to inhibitors for epidermal growth factor receptor (EGFR). Until now, clinical outcomes for HNSCC using EGFR inhibitors as single agents have yielded disappointing results. Here, we aimed to study whether combinatorial treatment using AG1478 (EGFR tyrosine kinase inhibitor) and deguelin, which is a rotenoid isolated from the African plant Mundulea sericea, could enhance the anti-tumor effects of AG1478 in HNSCC. For Ca9-22 cells with EGFR, KRAS, and PIK3CA wild types, AG1478 alone suppressed both phosphorylated levels of ERK and AKT and induced apoptosis. On the contrary, for HSC-4 cells with EGFR and KRAS wild types, and a PIK3CA mutant, AG1478 alone did not suppress the phosphorylated level of AKT nor induce apoptosis, while it suppressed ERK phosphorylation. Forced expression of constitutively active PIK3CA (G1633A mutation) significantly reduced the apoptotic effect of AG1478 on the PIK3CA wild-type Ca9-22 cells. When HSC-4 cells with the PIK3CA G1633A mutation were treated with a combination of AG1478 and deguelin, combination effects on apoptosis induction were observed through the inhibition of the AKT pathway. These results suggest that the combination of EGFR tyrosine kinase inhibitor with deguelin is a potential therapeutic approach to treat PIK3CA-mutated HNSCC.

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Section: Discussionmentioning

confidence: 99%

Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

Baba

Maeda

Suzuki

et al. 2017

IJMS

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“…Xiao et al (2016) found that miR-503 inhibited hepatocellular carcinoma cell growth, which is consistent with our results in which the Hep-mock cells had low cell viability with high miR-503 expression under the condition in which TNF-α was introduced for cell cultivation. Previous studies have demonstrated that TNF-α can activate NF-κB (Liu et al, 2015; Zhao et al, 2015), and NF-κB can promote miR-503 transcription (Caporali et al, 2015). Our results support those findings; we found that the expression of miR-503 and n65 were upregulated in the TNF-α-induced Hep-mock cells.…”

Section: Discussionmentioning

confidence: 99%

Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway

Xie

Xing

Wang

2017

Molecules and Cells

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The nonstructural protein 5A (NS5A) encoded by the human hepatitis C virus (HCV) RNA genome is a multifunctional phosphoprotein. To analyse the influence of NS5A on apoptosis, we established an Hep-NS5A cell line (HepG2 cells that stably express NS5A) and induced apoptosis using tumour necrosis factor (TNF)-α. We utilised the MTT assay to detect cell viability, real-time quantitative polymerase chain reaction and Western blot to analyse gene and protein expression, and a luciferase reporter gene experiment to investigate the targeted regulatory relationship. Chromatin immunoprecipitation was used to identify the combination of NF-κB and miR-503. We found that overexpression of NS5A inhibited TNF-αinduced hepatocellular apoptosis via regulating miR-503 expression. The cell viability of the TNF-α induced Hep-mock cells was significantly less than the viability of the TNF-α induced Hep-NS5A cells, which demonstrates that NS5A inhibited TNF-α-induced HepG2 cell apoptosis. Under TNF-α treatment, miR-503 expression was decreased and cell viability and B-cell lymphoma 2 (bcl-2) expression were increased in the Hep-NS5A cells. Moreover, the luciferase reporter gene experiment verified that bcl-2 was a direct target of miR-503, NS5A inhibited TNF-α-induced NF-κB activation and NF-κB regulated miR-503 transcription by combining with the miR-503 promoter. After the Hep-NS5A cells were transfected with miR-503 mimics, the data indicated that the mimics could reverse TNF-α-induced cell apoptosis and blc-2 expression. Collectively, our findings suggest a possible molecular mechanism that may contribute to HCV treatment in which NS5A inhibits NF-κB activation to decrease miR-503 expression and increase bcl-2 expression, which leads to a decrease in hepatocellular apoptosis.

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“…These inhibitory effects were mediated by the suppression of TNFα–induced activation of IκB kinase, which led to the inhibition of IκB phosphorylation, NF‐κB transcriptional activity, and matrix metalloproteinase 2 (MMP2) expression. This finding is crucial to increasing patient survival rates because cancer morbidity and mortality are chiefly attributed to cancer metastasis …”

Section: Anticancer Effects Of Deguelinmentioning

confidence: 99%

“…This finding is crucial to increasing patient survival rates because cancer morbidity and mortality are chiefly attributed to cancer metastasis. 54 Furthermore, Mehta et al 55 showed that deguelin treatment resulted in inhibition of the proliferation of 4T1 mammary cancer cells, which are highly aggressive estrogen receptor/progesterone receptor-and human epidermal growth factor receptor 2-negative cells that mimic stage IV breast cancer progression. In mouse models, deguelin also reduced the incidence of lung metastasis after intravenous 4T1 cell administration.…”

Section: Preventing Metastasismentioning

confidence: 99%

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

Varughese

Lam

Marican

et al. 2019

Cancer

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Deguelin is a rotenoid compound that exists in abundant quantities in the bark, roots, and leaves of the Leguminosae family of plants. An analysis of evidence from both in vitro and in vivo studies suggests that deguelin displays potent anticancer activity against multiple cancer types and exhibits chemopreventive potential in Akt‐inducible transgenic mouse models. Deguelin appears to impede carcinogenesis by enhancing cell apoptosis and hindering malignant transformation and tumor cell propagation. Crucial oncogenic pathways likely targeted by deguelin include the epithelial‐to‐mesenchymal transition; angiogenesis‐related pathways; and the phosphoinositide 3‐kinase/Akt, Wnt, epidermal growth factor receptor, c‐Met, and hedgehog signal transduction cascades. This review article provides a comprehensive summary of current preclinical research featuring deguelin as a leading chemotherapeutic and chemopreventive compound, and it highlights the importance of identifying companion molecular biomarkers and performing systemic pharmacokinetic studies for accelerating the process of developing deguelin as a clinical anticancer agent.

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Suppressive function of low‐dose deguelin on the invasion of oral cancer cells by downregulating tumor necrosis factor alpha–induced nuclear factor‐kappa B signaling

Abstract: The low-dose deguelin suppressed the invasion and migration of oral cancer by downregulating TNF-α-induced NF-κB signaling. © 2015 Wiley Periodicals, Inc. Head Neck 38: E524-E534, 2016.

Cited by 25 publications

References 42 publications

Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

Deguelin Potentiates Apoptotic Activity of an EGFR Tyrosine Kinase Inhibitor (AG1478) in PIK3CA-Mutated Head and Neck Squamous Cell Carcinoma

Hepatitis C Virus Nonstructural 5A Protein (HCV-NS5A) Inhibits Hepatocyte Apoptosis through the NF-κb/miR-503/bcl-2 Pathway

Biopharmacological considerations for accelerating drug development of deguelin, a rotenoid with potent chemotherapeutic and chemopreventive potential

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