Targeting the Ang2/Tie2 Axis with Tanshinone IIA Elicits Vascular Normalization in Ischemic Injury and Colon Cancer

Abstract

Pathological angiogenesis, as exhibited by aberrant vascular structure and function, has been well deemed to be a hallmark of cancer and various ischemic diseases. Therefore, strategies to normalize vasculature are of potential therapeutic interest in these diseases. Recently, identifying bioactive compounds from medicinal plant extracts to reverse abnormal vasculature has been gaining increasing attention. Tanshinone IIA (Tan IIA), an active component of Salvia miltiorrhiza, has been shown to play significant roles in improving blood circulation and delaying tumor progression. However, the underlying mechanisms responsible for the therapeutic effects of Tan IIA are not fully understood. Herein, we established animal models of HT-29 human colon cancer xenograft and hind limb ischemia to investigate the role of Tan IIA in regulating abnormal vasculature. Interestingly, our results demonstrated that Tan IIA could significantly promote the blood flow, alleviate the hypoxia, improve the muscle quality, and ameliorate the pathological damage after ischemic insult. Meanwhile, we also revealed that Tan IIA promoted the integrity of vascular structure, reduced vascular leakage, and attenuated the hypoxia in HT-29 tumors. Moreover, the circulating angiopoietin 2 (Ang2), which is extremely high in these two pathological states, was substantially depleted in the presence of Tan IIA. Also, the activation of Tie2 was potentiated by Tan IIA, resulting in decreased vascular permeability and elevated vascular integrity. Mechanistically, we uncovered that Tan IIA maintained vascular stability by targeting the Ang2-Tie2-AKT-MLCK cascade. Collectively, our data suggest that Tan IIA normalizes vessels in tumors and ischemic injury via regulating the Ang2/Tie2 signaling pathway.

Sodium tanshinone IIA sulphate inhibits angiogenesis in lung adenocarcinoma via mediation of miR-874/eEF-2K/TG2 axis

“…It was found that STS inhibited angiogenesis in colon cancer (Zou et al. 2021 ). Moreover, STS was able to attenuate the tumourigenesis of lung cancer (Li et al.…”

Co-Targeting Tumor Angiogenesis and Immunosuppressive Tumor Microenvironment: A Perspective in Ethnopharmacology

“…Uniformly, Tan IIA weakened VEGF/HIF-1α expression by controlling the mTOR /p70S6K /RPS6 /4E-BP1 axis in breast cancer ( Li et al, 2015 ). It was of importance that Tan IIA caused vascular stability and vascular normalization via downregulating Ang2-Tie2-AKT-MLCK axis in colon cancer ( Zou et al, 2021 ). The anti-angiogenic properties of tanshinone VI were attributed to its downregulation of adhesion molecules ICAM-1 and VCAM-1 in epithelial cells ( Nicolin et al, 2013 ).…”

Homologous-Magnetic Dual-Targeted Metal-Organic Framework to Improve the Anti-Hepatocellular Carcinoma Efficacy of PD-1 Inhibitor

“…[10][11][12] Tanshinone A (TSA), a diterpenoid compound from Salviae miltiorrhizae radix et rhizoma, has been demonstrated to inhibit the secretion of VEGF and regulate vascular normalisation. [13][14][15][16] Therefore, tumour vessel normalisation through TSA has the potential to increase the abundance of TILs. However, TILs still exhibit insu cient activity.…”