Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner

Sui, Tongtong; Qiu, Bojun; Qu, Jiaorong; Wang, Yuxin; Ran, Kunnian; Han, Wei; Peng, Xiaozhong

doi:10.1080/13880209.2021.1998140

Cited by 2 publications

(3 citation statements)

References 56 publications

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“…In addition, our earlier research showed that GA-amide could suppress angiogenesis. 24 Erin and colleagues found that GAamide could effectively suppress inflammation and enhance the immune response in breast carcinoma. 23 Thus, we suspected that GA-amide may have an impact not only on GSCs and GCs but also on the tumor microenvironment, including blood vessels and immune infiltrates.…”

Section: Discussionmentioning

confidence: 99%

“…21 Furthermore, GA-amide exhibited potential in cancer treatment by inhibiting leukemia cell proliferation and reducing leukemia progression in vivo; 22 while also markedly increasing interleukin 6 (IL-6) secretion and the interferon gamma (IFN-γ) response in breast carcinoma. 23 In our previous research, GA-amide was found to inhibit angiogenesis in a TrkA-independent manner, 24 which indicating that GA-amide might hold considerable potential as an inhibitor of cancer progression. Additionally, its neuroprotective properties rendered it advantageous for treating CNS diseases.…”

Section: Introductionmentioning

confidence: 94%

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The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

Qu,

Qiu,

Zhang

et al. 2023

Sig Transduct Target Ther

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Glioma is the most prevalent brain tumor, presenting with limited treatment options, while patients with malignant glioma and glioblastoma (GBM) have poor prognoses. The physical obstacle to drug delivery imposed by the blood‒brain barrier (BBB) and glioma stem cells (GSCs), which are widely recognized as crucial elements contributing to the unsatisfactory clinical outcomes. In this study, we found a small molecule, gambogic amide (GA-amide), exhibited the ability to effectively penetrate the blood-brain barrier (BBB) and displayed a notable enrichment within the tumor region. Moreover, GA-amide exhibited significant efficacy in inhibiting tumor growth across various in vivo glioma models, encompassing transgenic and primary patient-derived xenograft (PDX) models. We further performed a genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) knockout screen to determine the druggable target of GA-amide. By the combination of the cellular thermal shift assay (CETSA), the drug affinity responsive target stability (DARTS) approach, molecular docking simulation and surface plasmon resonance (SPR) analysis, WD repeat domain 1 (WDR1) was identified as the direct binding target of GA-amide. Through direct interaction with WDR1, GA-amide promoted the formation of a complex involving WDR1, MYH9 and Cofilin, which accelerate the depolymerization of F-actin to inhibit the invasion of patient-derived glioma cells (PDCs) and induce PDC apoptosis via the mitochondrial apoptotic pathway. In conclusion, our study not only identified GA-amide as an effective and safe agent for treating glioma but also shed light on the underlying mechanisms of GA-amide from the perspective of cytoskeletal homeostasis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

Qu,

Qiu,

Zhang

et al. 2023

Sig Transduct Target Ther

Self Cite

View full text Add to dashboard Cite

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“…In a xenograft model, GA treatment demonstrated a better inhibition on HUVEC cells than prostate cancer cells, suggesting the potential of GA as an anti-angiogenesis agent. Gambogic amide, a derivative of GA, has also been shown to inhibit angiogenesis, expression of VEGF, and the activation of VEGF/VEGFR2 signaling in HUVEC cells and normal human endothelial cells (NhEC) [ 22 ]. All the study results indicate the role of GA in angiogenesis in GC.…”

Section: Discussionmentioning

confidence: 99%

Gambogic Acid Inhibits Gastric Cancer Cell Proliferation through Necroptosis

Wang

Zhu

et al. 2023

Canadian Journal of Gastroenterology and Hepatology

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Gambogic acid (GA) is a natural xanthonoid secreted by Garcinia hanburyi tree. It possesses anti-cancer activity in various types of cancers. In gastric cancer, it inhibits cell proliferation through increasing apoptosis. However, whether necroptosis is involved in the GA-induced proliferation inhibited in gastric cancer is unknown. In the present study, we found that RIPK1 specific inhibitor necrostatin-1 (Nec-1) attenuated GA-induced proliferation inhibition. GA treatment increased the phosphorylation of necroptosis-related proteins, RIPK1, RIPK3, and MLKL, and their interactions to form the necrosome complex. The effector protein Drp-1 was dephosphorylated by GA treatment. Inhibition of necroptosis by different inhibitors and PGAM5 knockdown attenuated GA-induced cell death in gastric cancer cell lines, thereby attenuating GA-caused cell proliferation inhibition. All the data supported the conclusion that GA could inhibit gastric cancer cell proliferation by inducing necroptosis.

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Gambogic amide inhibits angiogenesis by suppressing VEGF/VEGFR2 in endothelial cells in a TrkA-independent manner

Cited by 2 publications

References 56 publications

The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

The tumor-enriched small molecule gambogic amide suppresses glioma by targeting WDR1-dependent cytoskeleton remodeling

Gambogic Acid Inhibits Gastric Cancer Cell Proliferation through Necroptosis

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