Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2‑mediated STAT3/PI3K/Akt signaling pathway

Shen, Mei; Zhou, Xuezhi; Ye, Lei; Yuan, Qing; Shi, Chaoji; Zhu, Pei‐Wen; Jiang, Nan; Ma, Mingyang; Yang, Qianying; Shao, Yi

doi:10.3892/ijmm.2018.3646

Cited by 14 publications

(19 citation statements)

References 33 publications

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“…(Asteraceae), a native herb commonly used in China [ 4 , 5 ]. Previous studies demonstrated that xanthatin exhibits a wide variety of bioactivities, including anticancer [ 6 , 7 ], antiangiogenesis [ 8 – 10 ], antiviral [ 10 ], antiinflammatory [ 11 ], antifungal [ 12 , 13 ], antibacterial [ 14 ], antitrypanosome [ 11 ], and antileishmanial [ 13 ] activities. In addition, xanthatin was reported to suppress proliferation and induce apoptosis in a wide variety of cancer cell culture systems, including non-small cell lung cancer cells (A549 and H522 cells), MKN-45 human gastric carcinoma cells, MDA-MB-231 human breast cancer cells, B16-F10 murine melanoma cells, and L1210 mouse leukemia cells [ 9 , 10 , 15 – 23 ].…”

Section: Introductionmentioning

confidence: 99%

Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway

Cao

et al. 2019

Acta Pharmacol Sin

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Xanthatin is a natural sesquiterpene lactone purified from Xanthium strumarium L. , which has shown prominent antitumor activity against a variety of cancer cells. In the current study, we investigated the effect of xanthatin on the growth of glioma cells in vitro and in vivo, and elucidated the underlying mechanisms. In both rat glioma C6 and human glioma U251 cell lines, xanthatin (1–15 μM) dose-dependently inhibited cell viability without apparent effect on the cell cycle. Furthermore, xanthatin treatment dose-dependently induced glioma cell apoptosis. In nude mice bearing C6 glioma tumor xenografts, administration of xanthatin (10, 20, 40 mg·kg −1 ·d −1 , ip, for 2 weeks) dose-dependently inhibited the tumor growth, but did not affect the body weight. More importantly, xanthatin treatment markedly increased the expression levels of the endoplasmic reticulum (ER) stress-related markers in both the glioma cell lines as well as in C6 xenografts, including glucose-regulated protein 78, C/EBP-homologous protein (CHOP), activating factor 4, activating transcription factor 6, spliced X-box binding protein-1, phosphorylated protein kinase R-like endoplasmic reticulum kinase, and phosphorylated eukaryotic initiation factor 2a. Pretreatment of C6 glioma cells with the ER stress inhibitor 4-phenylbutyric acid (4-PBA, 7 mM) or knockdown of CHOP using small interfering RNA significantly attenuated xanthatin-induced cell apoptosis and increase of proapoptotic caspase-3. These results demonstrate that xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating the ER stress-related unfolded protein response pathway involving CHOP induction. Xanthatin may serve as a promising agent in the treatment of human glioma.

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Section: Introductionmentioning

confidence: 99%

Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway

Cao

et al. 2019

Acta Pharmacol Sin

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“…Studies in LPS-injected mouse models have shown that AKTlinked STAT3 signaling contributes to the regulation of proinflammatory responses in the brain (6,7,68). Xanthatin, a VEGFRs and PDGFRb inhibitor, significantly reduces neuroinflammation by inhibiting AKT/PI3K/STAT3 signaling in a rat corneal alkali burn model (69). TKI258, another VEGFRs and PDGFRs inhibitor, reduces p-AKT and p-STAT3 levels in tumor xenograft nude mice (59).…”

Section: Discussionmentioning

confidence: 99%

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

Kim

Park

et al. 2021

Front. Immunol.

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Sorafenib is FDA-approved for the treatment of primary kidney or liver cancer, but its ability to inhibit many types of kinases suggests it may have potential for treating other diseases. Here, the effects of sorafenib on neuroinflammatory responses in vitro and in vivo and the underlying mechanisms were assessed. Sorafenib reduced the induction of mRNA levels of the proinflammatory cytokines COX-2 and IL-1β by LPS in BV2 microglial cells, but in primary astrocytes, only COX-2 mRNA levels were altered by sorafenib. Interestingly, sorafenib altered the LPS-mediated neuroinflammatory response in BV2 microglial cells by modulating AKT/P38-linked STAT3/NF-kB signaling pathways. In LPS-stimulated wild-type mice, sorafenib administration suppressed microglial/astroglial kinetics and morphological changes and COX-2 mRNA levels by decreasing AKT phosphorylation in the brain. In 5xFAD mice (an Alzheimer’s disease model), sorafenib treatment daily for 3 days significantly reduced astrogliosis but not microgliosis. Thus, sorafenib may have therapeutic potential for suppressing neuroinflammatory responses in the brain.

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“…Xanthatin inhibited the migration and lumen-forming ability of VEGF-treated HUVECs in a concentration-dependent manner and significantly decreased expression of phosphorylated (p-)VEGFR2, p-STAT3, p-PI3K, and p-Akt [123]. Topical xanthatin eye drops were used for the treatment of CoNV in a rat alkali burn model, and suppressed CoNV area, lowered VEGF, and raised PEDF protein levels [123]. Together, these results indicate that xanthatin likely inhibits CoNV through regulating the VEGFR2-mediated STAT3/PI3K/Akt signaling pathways.…”

Section: Non-flavonoid Phytochemicalsmentioning

confidence: 94%

“…Xanthatin's antiangiogenic effect and mechanism in CoNV were further evaluated with in vitro and in vivo studies. Xanthatin inhibited the migration and lumen-forming ability of VEGF-treated HUVECs in a concentration-dependent manner and significantly decreased expression of phosphorylated (p-)VEGFR2, p-STAT3, p-PI3K, and p-Akt [123]. Topical xanthatin eye drops were used for the treatment of CoNV in a rat alkali burn model, and suppressed CoNV area, lowered VEGF, and raised PEDF protein levels [123].…”

Section: Non-flavonoid Phytochemicalsmentioning

confidence: 99%

Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization

2020

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Under healthy conditions, the cornea is an avascular structure which allows for transparency and optimal visual acuity. Its avascular nature is maintained by a balance of proangiogenic and antiangiogenic factors. An imbalance of these factors can result in abnormal blood vessel proliferation into the cornea. This corneal neovascularization (CoNV) can stem from a variety of insults including hypoxia and ocular surface inflammation caused by trauma, infection, chemical burns, and immunological diseases. CoNV threatens corneal transparency, resulting in permanent vision loss. Mainstay treatments of CoNV have partial efficacy and associated side effects, revealing the need for novel treatments. Numerous natural products and synthetic small molecules have shown potential in preclinical studies in vivo as antiangiogenic therapies for CoNV. Such small molecules include synthetic inhibitors of the vascular endothelial growth factor (VEGF) receptor and other tyrosine kinases, plus repurposed antimicrobials, as well as natural source-derived flavonoid and non-flavonoid phytochemicals, immunosuppressants, vitamins, and histone deacetylase inhibitors. They induce antiangiogenic and anti-inflammatory effects through inhibition of VEGF, NF-κB, and other growth factor receptor pathways. Here, we review the potential of small molecules, both synthetics and natural products, targeting these and other molecular mechanisms, as antiangiogenic agents in the treatment of CoNV.

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Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2‑mediated STAT3/PI3K/Akt signaling pathway

Cited by 14 publications

References 33 publications

Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway

Xanthatin induces glioma cell apoptosis and inhibits tumor growth via activating endoplasmic reticulum stress-dependent CHOP pathway

Sorafenib Modulates the LPS- and Aβ-Induced Neuroinflammatory Response in Cells, Wild-Type Mice, and 5xFAD Mice

Pharmacological Potential of Small Molecules for Treating Corneal Neovascularization

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