Oridonin inhibits VEGF‑A‑associated angiogenesis and epithelial‑mesenchymal transition of breast cancer in�vitro and in�vivo

Abstract

Metastasis is the primary cause of mortality in patients with breast cancer and lacks effective therapeutic agents. Oridonin, an active diterpenoid compound isolated from Rabdosia rubescens, was identified to be the most potent anti-tumor ingredient. However, the molecular mechanisms responsible for its anti-metastatic effects remain unclear. In the present study, oridonin significantly suppressed the migration, invasion and adhesion of MDA-MB-231 and 4T1 breast cancer cells, and inhibited tube formation of human umbilical vein endothelial cells in a dose-dependent manner. The expression levels of epithelial-mesenchymal transition (EMT)-associated marker and the hypoxia inducible factor 1α (HIF-1α)/vascular endothelium growth factor (VEGF) signaling pathway mRNA and proteins were determined by reverse transcription-quantitative polymerase chain reaction and western blotting, respectively in vitro. The results demonstrated that oridonin effectively inhibited EMT as demonstrated by the significant increases in the expression levels of E-cadherin, and decreased expression of N-cadherin, Vimentin and Snail. In addition, oridonin exerted its anti-angiogenesis activity through significantly decreasing HIF-1α, VEGF-A and VEGF receptor-2 protein expression. Furthermore, oridonin was demonstrated to decrease the micro-vessel density as evidenced by the decreased expression of cluster of differentiation 31, a marker for neovasculature. In brief, oridonin inhibits tumor cell migration, invasion and adhesion, as well as tumor angiogenesis, which are mediated by suppressing EMT and the HIF-1α/VEGF signaling pathway. The results of the present study suggest that oridonin may be a promising anti-metastatic agent in breast cancer treatment.

Oridonin inhibits the migration and epithelial‐to‐mesenchymal transition of small cell lung cancer cells by suppressing FAK‐ERK1/2 signalling pathway

“…In our study, the expression of E‐cadherin was reduced in SCLC; however, the expression of E‐cadherin was increased after the application of oridonin. As previous studies have found that cell migration and EMT were inhibited by oridonin in pancreatic cancer and breast cancer, we have been suggested that the effect of oridonin on inhibiting EMT is associated with increased E‐cadherin expression.…”

Naturally occurring anti-cancer compounds: shining from Chinese herbal medicine

“…As an orally available drug, oridonin is demonstrated to have anti-cancer activities in multiple cancers over the past decades, including leukemia, lymphoma, osteosarcoma, myeloma, uveal melanoma, neuroblastoma, hepatocellular, laryngeal, esophageal, and oral squamous cell carcinoma, lung, colorectal, breast, gastric, pancreatic, and prostatic cancers [543][544][545][546][547][548][549][550][551][552][553][554][555][556][557][558]. The anti-cancer effects of oridonin are shown in many aspects, including the induction of cell apoptosis, autophagy, cell cycle arrest, and the suppression of angiogenesis, cell migration, invasion and adhesion [554,[559][560][561][562][563][564].…”

“…The anti-cancer effects of oridonin are also shown to be through suppressing angiogenesis and metastasis, which are the primary causes of tumor growth and metastasis. It can inhibit cell migration and invasion, and tube formation in human breast cancer 4T1 and MDA-MB-231, human and murine melanoma A375 and B16F10, osteosarcoma MG63 and 143B, and HUVECs, as well as tumor metastasis in HepG2 xenograft zebrafish and mice, 4T1 xenograft mice, and 143B xenograft mice [554,[562][563][564]573].…”

<p>HIF-1α is a Potential Molecular Target for Herbal Medicine to Treat Diseases</p>

“…110 Another diterpene compound, oridonin, derived from the TCM of Rabdosiae rubescentis Herba, has anti-metastatic effect in breast cancer treatment by inhibiting epithelialmesenchymal transition (EMT) and the HIF-1α/VEGF signaling pathway. After treatment with oridonin, the expression of E-cadherin decreased, while the expression of N-cadherin, Vimentin, Snail, HIF-1 α, VEGF-A and VEGFR2 increased.- 111 Polysaccharides are a class of macromolecular substances composed of a large number of monosaccharides, some of which have significant inhibitory effects on HIF-1α. For example, fucoidan extracted from Brown seaweed is a kind of sulfated polysaccharide, which has a significant therapeutic effect on mammary cancer.…”