Efficient synthesis of new phenanthridine Wnt/β-catenin signaling pathway agonists

Chen, Duozhi; Zhang, Heng; Jing, Chuanyong; He, Xiaoli; Yang, Bo; Cai, Jiangping; Zhou, Yunfu; Song, Xiaoming; Lin, Li; Hao, Xiao‐Jiang

doi:10.1016/j.ejmech.2018.08.064

Cited by 10 publications

(3 citation statements)

References 11 publications

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“…HLY78 is a new small-molecule activator of the Wnt/β-catenin signaling pathway, that acts in a Wnt ligand-dependent manner. Mounting evidence suggests that HLY78 directly binds to the DAX domain of Axin, enhancing the interaction of Axin-LRP6, which promotes LRP6 phosphorylation and Wnt signal transduction (32)(33)(34). A previous study has revealed that zebrafish embryo supplementation with HLY78 significantly reduced developmental toxicity induced by carbon ion radiation alone (34).…”

Section: The Effects Of the Wnt/β-catenin Signaling Pathway On Apoptosis In Hela Cells Induced By Carbon Ion Irradiationmentioning

confidence: 99%

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

Zhang

Gan

et al. 2020

Oncol Rep

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The molecular mechanisms underlying the biological effects of carbon ions are unclear. The aim of this study was to explore the Wnt/β-catenin pathway in regulating carbon ion ( 12 C 6+ ) radiation-induced cellular toxicity. HLY78 is a Wnt-specific small molecular modulator, whose effects on 12 C 6+ radiation-induced damage are mostly unknown. HLY78, in combination with 12 C 6+ radiation was investigated on HeLa cell viability, cell cycle progression, DNA damage, and the expression of apoptotic and Wnt-related proteins. 12 C 6+ radiation suppressed cell viability in a time-dependent manner, whereas the addition of HLY78 to cells significantly reduced this stress. Moreover, after irradiation with 12 C 6+ , HeLa cells exhibited increased cell apoptosis, G2/M phase arrest, and a number of γ-H2AX foci. However, Wnt signaling activation alleviated these effects. Furthermore, when compared with the radiation alone group, supplementation with HLY78 markedly increased the expression of anti-apoptotic and Wnt-related proteins, and significantly decreased the expression of apoptotic proteins. The present results indicated that activation of the Wnt/β-catenin signaling pathway by HLY78 reduced 12 C 6+ radiation-induced HeLa cell dysfunction, suggesting that the Wnt/β-catenin signaling pathway plays an important role in regulating 12 C 6+ radiation-induced cellular toxicity in HeLa cells.

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Section: The Effects Of the Wnt/β-catenin Signaling Pathway On Apoptosis In Hela Cells Induced By Carbon Ion Irradiationmentioning

confidence: 99%

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

Zhang

Gan

et al. 2020

Oncol Rep

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“…[ 11 ]. Increasing evidence shows that the Wnt/β-catenin signaling pathway is the main oncogenic pathway of ESCC [ 12 ]. Wnt signaling induces EZH2 binding to β-catenin, regulating of the epitranscriptome, including c-Myc [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Ginsenoside Rh4 Suppresses Metastasis of Esophageal Cancer and Expression of c-Myc via Targeting the Wnt/β-Catenin Signaling Pathway

et al. 2022

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The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.

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“…Our previous research identified a new series of phenanthridine-specific agonists of the Wnt/β -catenin signalling pathway (Wang et al, 2013;Chen et al, 2018;Chen et al, 2016;Chen et al, 2019). In consideration of the role of Wnt in melanogenesis, it is worth discussing whether appropriate, potent phenanthridine Wnt agonists have the potential to cure or improve the symptoms of vitiligo.…”

Section: Introductionmentioning

confidence: 99%

Axin, the classic scaffold protein of Wnt/β-catenin signalling as a potential drug-target for vitiligo

Chen

Fan

et al. 2020

Preprint

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Background and Purpose: Humans have been fighting vitiligo for centuries but still being inferior due to the lack of efficiency drugs and therapies. While some research has implied the therapeutic potential of Wnt/β-catenin signalling on curing vitiligo but correlation mechanism is not clear and no Wnt-specific anti-vitiligo drug has been reported. Here, We identified how vitiligo could be treated by regulating Wnt and two lead compounds of new anti-vitiligo drugs have been found. Experimental Approach: Wnt agonists were rational synthesized and then be evaluated their effects on vitiligo in B16 cells and C57B/L mouse. Furthermore, Co-IP and Site-directed mutagenesis were employed to indicate the mechanism and the target of the compounds. Key Results: HCJA121 and HCJA404 could significantly promote the synthesis of melanin, restore the pigmented function of skin, and improve the symptoms of vitiligo. Mechanism studies indicated that HCJA121 and HCJA404 target the DAX domain of Axin by binding to LYS781 and LEU784 then potentiate the Axin-LRP6 association and eventually promoted melanogenesis. Conclusions and Implications: These findings imply an alternative regulatory mechanism of melanogenesis and the Axin protein could be a new target for anti-vitiligo agents which reveal a therapeutic strategy for vitiligo. Besides, HCJA121 and HCJA404 may represent potential compounds for vitiligo treatment.

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Efficient synthesis of new phenanthridine Wnt/β-catenin signaling pathway agonists

Cited by 10 publications

References 11 publications

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

The effects of the Wnt/β‑catenin signaling pathway on apoptosis in HeLa cells induced by carbon ion irradiation

Ginsenoside Rh4 Suppresses Metastasis of Esophageal Cancer and Expression of c-Myc via Targeting the Wnt/β-Catenin Signaling Pathway

Axin, the classic scaffold protein of Wnt/β-catenin signalling as a potential drug-target for vitiligo

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