Triptonide effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways

Xiang, Shufen; Zhao, Zhe; Zhang, Tong; Zhang, Bin; Meng, Mei; Cao, Zhifei; Zhou, Quansheng

doi:10.1016/j.taap.2019.114870

Cited by 30 publications

(27 citation statements)

References 39 publications

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“…Xiang et al 31 prove that TN effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways. In this study, we attempted to explore the growth inhibitory effect of triptonide in osteosarcoma cells and found that triptonide at nano-scale concentration dramatically inhibited the…”

Section: Discussionmentioning

confidence: 99%

Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells

Fang¹,

Jing²,

Rajamanickam³

et al. 2020

CMAR

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Background: Osteosarcoma (OS) is the most common primary malignancy arise from bone and is one of the causes of cancer-related deaths. Triptonide (TN), a diterpenoid epoxide presented in Tripterygium wilfordii, is shown to possess a broad spectrum of biological properties. Methods: In this study, we investigate the growth inhibitory effect of TN against human OS cells and its underlying molecular mechanism of action. Results: Findings of our in vitro study revealed that TN exhibited a dose-dependent cytotoxic effect in MG63 and U-2OS cells. ROS-mediated cytotoxic effect was achieved in OS cells treated with TN which was reversed upon NAC treatment. Significantly, increased expression of PERK, p-EIF2, GRP78, ATF4 and CHOP in TN-treated OS cells unfolds the molecular mechanism of TN targets ER stress-mediated apoptosis. Modulation of ERK MAPK pathway was also observed as evidenced by the increased phosphorylation of ERK (p-ERK) and p-p38 in TN-treated OS cells. Conclusion: Altogether, the outcome of the study for the first time revealed that TN exhibited its potential chemotherapeutic effects through ROS-mediated ER stress-induced apoptosis via p38 and ERK MAPK signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells

Fang¹,

Jing²,

Rajamanickam³

et al. 2020

CMAR

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“…MDA-MB-231 and MDA-MB-468 cells were rst seeded onto glass cover slips for 24h, then treated with triptonide at the concentrations of 0-10 nM for 72 h. The cells were xed with 4% paraformaldehyde and incubated with primary antibody against Twist1 at 4°C overnight, followed by incubation with secondary antibodies, counterstained with 4, 6-diamidino-2-phenylindole (DAPI), and subjected to be imaged under confocal microscopy [34].…”

Section: Immuno Uorescence Microscopymentioning

confidence: 99%

“…It was recently reported that triptonide exerts strong inhibitory effects on acute myeloid leukemia, lymphoma, lung cancer, gastric cancer, and pancreatic cancer via reducing cancer cell stemness and oncogenic signaling pathways, and suppressing cancer cell tumorigenesis and vasculogenic mimicry [30][31][32][33][34][35][36]. More recently, Gao B., et al reported that triptonide inhibits TNBC cell tumorigenesis via downregulation of several cancer stem cell-associated genes, up-regulation of Snail1 expression, and induction of a Snail1-associated feedback mechanism for triptonide resistance [37].…”

Section: Introductionmentioning

confidence: 99%

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

Zhang

Meng

Liu

et al. 2021

Preprint

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Background: Triple-negative breast cancer (TNBC) is highly metastatic and lethal. Due to a lack of druggable targets for this disease, there are no effective therapies in the clinic.Methods: We explored the ability of active compounds derived from natural herbs to inhibit TNBC metastasis using the methods of molecular biology, cell biology, protein chemistry, pharmacology, and xenografted mice.Results: Here, we showed that triptonide, a small molecule from the traditional Chinese medicinal herb Tripterygium wilfordii Hook F, potently inhibited TNBC cell migration, invasion, and vasculogenic mimicry, and effectively suppressed TNBC tumor growth and lung metastasis in xenografted mice with no observable toxicity. Molecular mechanistic studies revealed that triptonide strongly triggered the degradation of master epithelial-mesenchymal transition (EMT)-inducing protein Twist1 through the lysosomal system and reduced Notch1 expression and NF-κB phosphorylation, which consequently diminished the expression of pro-metastatic and angiogenic genes N-cadherin, VE-cadherin, and vascular endothelial cell growth factor receptor 2 (VEGFR2).Conclusions: Triptonide effectively suppressed TNBC cell tumorigenesis, vasculogenic mimicry, and strongly inhibited the metastasis of TNBC via degradation of Twist1 and Notch1 oncoproteins, downregulation of metastatic and angiogenic gene expression, and reduction of NF-κB signaling pathway. Our findings provide a new strategy for treating highly lethal TNBC and offer a potential new drug candidate for combatting this aggressive disease.

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“…1,3,15 TPN acts as a novel potent anticancer drugs with low toxicity. [16][17][18][19] The differences between the chemical structures of TPL and TPN are the substituent groups at C-14 position in which TPL is with C-14-hydroxyl and TPN is with C-14-carbonyl ( Figure 1A and B). The metabolomics study shows that the hydroxyl group at C-14 in the molecular structure of TPL plays an important role in its hepatotoxicity.…”

Section: Introductionmentioning

confidence: 99%

Intravenous Administration of Triptonide Attenuates CFA-Induced Pain Hypersensitivity by Inhibiting DRG AKT Signaling Pathway in Mice

Ling¹,

Ding²,

Dong³

et al. 2020

JPR

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Background: Currently, medical treatment of inflammatory pain is limited by a lack of safe and effective therapies. Triptonide (TPN), a major component of Tripterygium wilfordii Hook.f. with low toxicity, has been shown to have good anti-inflammatory and neuroprotective effects. The present study aims to investigate the effects of TPN on chronic inflammatory pain. Materials and Methods: Inflammatory pain was induced by intraplantar injection of complete Freund's adjuvant (CFA). TPN's three different doses were intravenously administered to compare the analgesic efficacy: 0.1 mg/kg, 0.5 mg/kg, and 2.0 mg/kg. The foot swelling was quantitated by measuring paw volume. Mechanical allodynia and thermal hyperalgesia were assessed with von Frey filament testing and Hargreaves' test, respectively. Western blots, qRT-PCR and immunofluorescence tests were used to analyze the expression of pAKT, tumor necrosis factor-α (TNF-α), interleukin 1 beta (IL-1β), and interleukin 6 (IL-6). Two AKT inhibitors, AKT inhibitor Ⅳ and MK-2206, were used to examine AKT's effects on pain behavior and cytokines expression. Results: Intravenous treatment with TPN attenuated CFA-induced paw edema, mechanical allodynia, and thermal hyperalgesia. Western blotting and immunofluorescence results showed that CFA induced AKT activation in the dorsal root ganglion (DRG) neurons. However, these effects were suppressed by treatment with TPN. Furthermore, TPN treatment inhibited CFA-induced increase of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6. Consistent with the in vivo data, TPN inhibited LPS-induced Akt phosphorylation and inflammatory mediator production in ND7/23 cells. Finally, intrathecal treatment with AKT inhibitor Ⅳ or MK-2206, attenuated CFA-induced mechanical allodynia and thermal hyperalgesia, and simultaneously decreased the mRNA expression of TNF-α, IL-1β, and IL-6 in DRG. Conclusion: These data indicate that TPN attenuates CFA-induced pain potentially via inhibiting AKT-mediated pro-inflammatory cytokines production in DRG. TPN may be used for the treatment of chronic inflammatory pain.

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Triptonide effectively suppresses gastric tumor growth and metastasis through inhibition of the oncogenic Notch1 and NF-κB signaling pathways

Cited by 30 publications

References 39 publications

<p>Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells</p>

<p>Triptonide Modulates MAPK Signaling Pathways and Exerts Anticancer Effects via ER Stress-Mediated Apoptosis Induction in Human Osteosarcoma Cells</p>

Triptonide Effectively Inhibits Triple-Negative Breast Cancer Metastasis Through Concurrent Degradation Of Twist1 And Notch1 Oncoproteins

<p>Intravenous Administration of Triptonide Attenuates CFA-Induced Pain Hypersensitivity by Inhibiting DRG AKT Signaling Pathway in Mice</p>

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