Antiangiogenic effects of AG36, a triterpenoid saponin from Ardisia gigantifolia stapf.
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ORIGINAL PAPER
Antiangiogenic effects of AG36, a triterpenoid saponin from Ardisia gigantifolia stapf. Li‑Hua Mu1 · Li‑Hua Wang1 · Yu‑Ning Wang2 · Ping Liu1 · Can Yan3,4 Received: 18 September 2019 / Accepted: 22 June 2020 © The Japanese Society of Pharmacognosy 2020
Abstract AG36 is a triterpenoid saponin from Ardisia gigantifolia stapf. Our recent studies proved that AG36 displayed prominent cytotoxicity against breast cancer cells both in vitro and in vivo. However, whether AG36 has antiangiogenic properties is unknown. Therefore, in the present study, we evaluated the antiangiogenic effect of AG36 and the underlying mechanism. The results indicated that AG36 could significantly inhibit the proliferation, migration and invasion of human umbilical vein endothelial cells (HUVEC). Further antiangiogenic molecular mechanism investigation showed that AG36 significantly suppressed phosphorylated FAK and AKT, and downregulated the expressions of vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) in HUVECs. PI3K inhibitor (LY294002) and FAK inhibitor (PF562271) pretreatment could markedly enhance AG36-induced inhibition of HUVEC proliferation and p-FAK suppression, respectively. In addition, AG36 inhibited the tumor growth in xenograft model and expressions of p–VEGFR2 and p–Akt in vivo. Molecular docking simulation indicated that AG36 formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. The present study firstly revealed the high antiangiogenic potency and related underlying molecular of AG36, demonstrating that AG36 maybe a potential antiangiogenic cancer therapy agent or lead candidate.
Keywords Ardisia gigantifolia · Triterpenoid saponin · Human umbilical vein endothelial cells · Antiangiogenic activity · Molecular docking Li-Hua Mu and Li-Hua Wang contributed equally to this work.
Introduction
* Ping Liu [email protected]
The rhizome of Ardisia gigantifolia stapf. is a traditional Chinese medicine used to treat traumatic injury, rheumatism, muscles, and bones pain. The antitumor activities about this plant were reported recently [1, 2]. As part of our ongoing
* Can Yan [email protected] Extended author information available on the last page of the article
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Vol.:(0123456789)
Journal of Natural Medicines
work to discover new anticancer lead compounds, we have isolated a series of triterpenoid saponins from A. gigantifolia stapf., most of them showed cytotoxicity against different kinds of cancer cells [3–6]. One of the isolated triterpenoid saponin AG4 was biotransformated by Alternaria alternata AS 3.6872 to obtain AG36 (Fig. 1a) [7]. Our previous study showed that AG36 exerted prominent cytotoxicity against breast cancer cells both in vitro and in vivo [8]. Recently, several studies have shown that some natural triterpenoid saponins display antiangiogenic properties, including inhibition of proliferation, migration, invasion and tube formation in cancer cells and the microvessels formation in anim
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