Antitumor Effects of Trimethylellagic Acid Isolated From Sanguisorba officinalis L. on Colorectal Cancer via Angiogenesis Inhibition and Apoptosis Induction

Abstract

Previous studies have demonstrated that tannin could inhibit the proliferation and angiogenesis of cancer cells. However, the mechanism(s) associated with its antitumor effect remains unclear. Here, we investigated the effects of 3,3',4'-trimethylellagic acid (TMEA), a tannin compound isolated from Sanguisorba officinalis L., on the proliferation, angiogenesis, and apoptosis in cancer cells, as well as the underlying mechanism(s) related to its antitumor activity. TMEA was isolated from Sanguisorba officinalis L. by silica gel column chromatography. Molecular docking was carried out to assess active pocket binding between TMEA and vascular endothelial growth factor receptor 2 (VEGFR2). The antiangiogenic effect of TMEA on the migration and tube formation was detected in HUVECs by wound healing and tube formation assays, respectively. The antitumor effects of TMEA on the cell proliferation were determined in HepG2, A549, and SW620 cells by MTS assay in vitro and on the tumor growth of SW620 xenografts bearing in nude mice in vivo. The mRNA expression of Bcl-2, Bax, caspase-3, VEGF, PI3K, and mTOR were measured by qRT-PCR and protein expression of Bcl-2, Bax, caspase-3, VEGF, PI3K, and mTOR by Western blotting, and the protein expression of Bcl-2, Bax, caspase-3 and CD31 were detected by immunohistochemical analysis in vivo, respectively. The results showed that TMEA combined with VEGFR2 in the functional pockets of Asn223A, Gly922A, and Leu840A and inhibited the proliferation, migration, tube formation, and expression of VEGF and its downstream signaling mediators in HUVECs. TMEA also significantly inhibited the proliferation of HepG2, A549, and SW620 cancer cells in vitro, and suppressed the growth of SW620 tumors in vivo. Moreover, TMEA upregulated the expression of proapoptotic factors Bax and caspase-3 and downregulated the expression of antiapoptotic factors CD31 and Bcl-2 in cancer cells and/or tumor tissues. The data indicate that TMEA executes its anticancer activity by inducing

Network Pharmacology and Pharmacological Evaluation Reveals the Mechanism of the Sanguisorba Officinalis in Suppressing Hepatocellular Carcinoma

“…It was reported that a hot water preparation made of a single herb (SO) has excellent antitumor effect in human oral cancer cells ( Shin et al, 2012 ). Moreover, triterpenoids and tannins isolated from the roots of SO have been shown promising antitumor effects in several cancer researches ( Liu et al, 2005 ; Bai et al, 2019 ; Li et al, 2019 ). Notably, it was reported recently that Ziyuglycoside II, a major active compound of SO, markedly impaired HepG2 proliferation, migration and invasion, by blocking EGFR/NF-kB signaling ( Liao et al, 2020 ).…”

Sanguisorba officinalis L. Suppresses Triple-Negative Breast Cancer Metastasis by Inhibiting Late-Phase Autophagy via Hif-1α/Caveolin-1 Signaling

“…Specifically, TCM has been widely used as a pool filed with abundant novel therapeutic agents for approximately 63–83% of patients with breast cancer, owing to its favorable efficacies, accessible availability, and limited adverse effects ( Liu et al, 2019 ; Yang et al, 2019 ). Sanguisorba officinalis L (SA, Chinese name as Di Yu; The voucher number/barcode 2,896,446) is traditionally prescribed for cancer prevention and treatment that putatively works by reducing blood toxicity and enhancing immunity in patients ( Bai et al, 2019 ). In our early study, we found SA exerted an obvious inhibitory effect on breast cancer angiogenesis, which is known to represent the basis of tumor growth, invasion, and metastasis ( Wang et al, 2012b ).…”

A Bioactive Compound from Sanguisorba officinalis L. Inhibits Cell Proliferation and Induces Cell Death in 5-Fluorouracil-Sensitive/Resistant Colorectal Cancer Cells

“…Gallic acid, a major compound of phenols in Sanguisorba officinalis L., could bind to ferroptosis-related targets and regulate the expression of corresponding proteins; ferroptosis inhibitors reversed the experimental results, improving CRC by regulating ferroptosis [24]. Another compound named 3,3 ,4trimethylellagic acid (TMEA), a tannin compound isolated from Sanguisorba officinalis L., executed its anti-cancer activity by inducing apoptosis and inhibiting angiogenesis in CRC cells via the apoptotic and VEGF/PI3K/AKT/mTOR pathways [25]. A type of tannin compound named 1,4,6-Tri-O-galloyl-beta-d-glucopyranose significantly inhibited the Wnt/beta-catenin signaling pathway, up-regulated the protein levels of cleaved caspase-3 and cleaved PARP, as well as the ratio of Bax/Bcl-2 proteins in HT29 cell [26].…”