Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling

Wan, Jianfeng; Liu, T; Mei, Liufeng; Li, J; Gong, Kan; Yu, Chunrong; Li, W

doi:10.1038/bjc.2013.334

Cited by 85 publications

(64 citation statements)

References 52 publications

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“…Specifically, stress appears to activate the Akt signal transduction pathway in tumor cells, which results in protective autophagy (8,27). Therefore, to determine the involvement of the Akt signaling pathway in the effect of the above combined treatment, the levels of protein phosphorylation were detected by western blotting (Fig.…”

Section: Akt Signaling Pathway Is Involved In the Effect Of The Combimentioning

confidence: 99%

“…In addition, an Akt inhibitor could cause a switch from protective autophagy to autophagic cell death. This switch enhanced sorafenib resistance and cell proliferation in RCC cells (8,26,27). However, similar studies on RCC radiotherapy are rare.…”

Section: Introductionmentioning

confidence: 98%

“…Patients presenting with advanced RCC have a poor prognosis due to the chemo-and radioresistance of this disease (2,3). Specifically, tumor cells respond to radiation via multiple growth arrests and a form of protective autophagy (4)(5)(6)(7)(8). Therefore, radiotherapy is rarely used to treat RCC in the clinic (9), and novel anti-tumor agents to reverse the radiosensitivity of RCC are urgently required.…”

Section: Introductionmentioning

confidence: 99%

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Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

et al. 2016

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Abstract. Renal cell carcinoma (RCC) is resistant to standard radiotherapy. Ubenimex, an aminopeptidase N inhibitor, is widely used as an adjunct therapy after surgery to enhance the function of immunocompetent cells and confer antitumor effects. Our previous study demonstrated that ubenimex induces autophagic cell death in RCC cells. Recently, the molecular mechanism of autophagy induction has been associated with radiosensitivity in RCC cells. In the present study, the ability of ubenimex to enhance RCC cell sensitivity to radiation via the induction of autophagic cell death was determined, and the mechanism of action of this effect was investigated. The 786-O and OS-RC-2 human RCC cell lines were treated with 0.5 mg/ml ubenimex and different doses of irradiation (IR). The cell viability was measured using a colony-formation assay and flow cytometry. Acridine orange (AO)-ethidium bromide (EB) staining was assessed by fluorescence microscopy as an indicator of autophagic cell death. Protein expression was assessed by western blotting. Autophagosomes were evaluated using transmission electron microscopy. RCC cells were used to evaluate the sensitivity to radiation using clonogenic survival and lactate dehydrogenase assays. Furthermore, these parameters were also tested at physiological oxygen levels.

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Section: Akt Signaling Pathway Is Involved In the Effect Of The Combimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

et al. 2016

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“…It has been shown that tumor cell apoptosis caused by tetrandrine exhibits inhibitory effects on various types of tumor cell (24)(25)(26)(27)(28)(29). The results of the present study indicated that tetrandrine had no cytotoxic effect on the HT29 cells, however, the anti-metastatic effect of tetrandrine on EGF-induced HT29 cancer cells was observed, and the underlying molecular signaling was evaluated.…”

Section: Discussionmentioning

confidence: 57%

“…Tetrandrine has been shown to have broad pharmacological actions (20)(21)(22). Several reports have indicated that tetrandrine presents potent anticancer effects on multiple cancer cells in vitro (23)(24)(25)(26)(27)(28)(29). Tetrandrine retards Wnt/β-catenin signaling and inhibits tumor growth of HCT116 human colorectal cancer (24).…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Horng

Yang

Chiang³

et al. 2015

Molecular Medicine Reports

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Abstract.Tetrandrine has been shown to reduce cancer cell proliferation and to inhibit metastatic effects in multiple cancer models in vitro and in vivo. However, the effects of tetrandrine on the underlying mechanism of HT29 human colorectal adenocarcinoma cell metastasis remain to be fully elucidated. The aim of the present study was focused on tetrandrine-treated HT29 cells following epidermal growth factor (EGF) treatment, and Transwell, gelatin zymography, gene expression and immunoblotting assays were performed to investigate metastatic effects in vitro. Tetrandrine was observed to dose-dependently inhibit EGF-induced HT29 cell invasion and migration, however, no effect on cell viability occurred following exposure to tetradrine between 0.5 and 2 µM. Tetrandrine treatment inhibited the enzymatic activity of matrix metalloprotease (MMP)-2 and MMP-9 in a concentration-dependent manner. The present study also found a reduction in the mRNA expression levels of MMP-2 and MMP-9 in the tetrandrine-treated HT29 cells. Tetrandrine also suppressed the phosphorylation of EGF receptor (EGFR) and its downstream pathway, including phosphoinositide-dependent kinase 1, phosphatidylinositol 3-kinase and phosphorylated AKT, suppressing the gene expression of MMP-2 and MMP-9. Furthermore, tetrandrine triggered mitogen-activated protein kinase signaling through the suppressing the activation of phosphorylated extracellular signal-regulated protein kinase. These data suggested that targeting EGFR signaling and its downstream molecules contributed to the inhibition of EGF-induced HT29 cell metastasis caused by tetrandrine, eventually leading to a reduction in the mRNA and gelatinase activities of MMP-2 and MMP-9, respectively. IntroductionEpidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases (1), and EGFR activation by ligand binding stimulates multiple signals, including phosphatidylinositol 3-kinase (PI3K)/AKT, mitogen-activated protein kinases (MAPKs) and nuclear factor-κB pathways, ultimately resulting in cellular proliferation, survival, angiogenesis invasion and metastasis (2,3). Abnormal protein activity and/or expression levels of EGFR have been correlated with the etiology of several types of human cancer, including colorectal cancer (4,5), non-small cell lung cancer (6,7), breast cancer (8,9), head and neck squamous cell carcinoma (10,11), pancreatic cancer (12) and brain cancer (13). EGFR-targeted therapy has been validated in human colorectal cancer (14), and the chemotherapeutics include pharmacological agents, including cetuximab (Erbitux), which is an EGFR inhibitor (15). EGFR acts to bind an EGFR-selective ligand activated by epidermal growth factor (EGF), transforming growth factor-α, amphiregulin or neuregulin, finally leading to cell proliferation, invasion and the inhibition of apoptosis (15)(16)(17).Tetrandrine is a bisbenzylisoquinoline alkaloid, which is isolated from the dried root of Stephania tetrandra of the

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Tetrandrine, a novel inhibitor of ether‐à‐go‐go‐1 (Eag1), targeted to cervical cancer development

Wang

Chen

et al. 2018

Journal Cellular Physiology

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Mortality-to-incidence ratios in patients with cancer are extremely high, positioning cancer as a major cause of death worldwide. Ether-à-go-go-1 (Eag1) is an ion channel that plays important roles in tumour proliferation, malignant transformation, invasion, metastasis, recurrence, and prognosis. Therefore, identifying potent and specific Eag1 channel inhibitors is crucial. In this study, we identified the first natural inhibitor of Eag1, the traditional Chinese medicine agent tetrandrine, and explored the underlying mechanism. Tetrandrine directly interacted with Eag1 and inhibited the currents in a concentration-dependent manner (IC 50 of 69.97 ± 5.2 μM), and the amino acids Ile 550 , Thr 552 , and Gln 557 in the Eag1 C-linker domain were critical for tetrandrine's inhibitory effect. Moreover, tetrandrine reduced the proliferation of HeLa cells and Chinese hamster ovary (CHO) cells stably expressing Eag1 in a concentrationdependent manner. Finally, tetrandrine (30 mg/kg/day) inhibited tumor growth in mice, demonstrating a 64.21% inhibitory rate of HeLa cell-transplanted tumors. These results suggest that tetrandrine is a potent and selective Eag1 channel inhibitor, and could act as a leading compound in the development of therapies for Eag1 ion channel dysfunction-induced diseases.

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Synergistic antitumour activity of sorafenib in combination with tetrandrine is mediated by reactive oxygen species (ROS)/Akt signaling

Cited by 85 publications

References 52 publications

Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

Ubenimex enhances the radiosensitivity of renal cell carcinoma cells by inducing autophagic cell death

Inhibitory effects of tetrandrine on epidermal growth factor-induced invasion and migration in HT29 human colorectal adenocarcinoma cells

Tetrandrine, a novel inhibitor of ether‐à‐go‐go‐1 (Eag1), targeted to cervical cancer development

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