Astragali Radix-Curcumae Rhizoma normalizes tumor blood vessels by HIF-1α to anti-tumor metastasis in colon cancer

Abstract

Background

Abnormal tumor blood vessels can significantly promote the malignant progression of tumors, prompting researchers to focus on drugs that normalize these vessels for clinical treatment. The combination of the Qi-tonifying drug Astragali Radix and the blood-activating drug Curcumae Rhizoma, referred to as AC, exhibited significant anti-tumor metastasis effects. However, the association between the anti-tumor metastasis effect of AC and its potential role in regulating tumor vascular remodeling warrants further exploration.

Purpose

This study aimed to elucidate the mechanism through which AC induces tumor blood vessel normalization in colon cancer (CC).

Methods

The potential active components of AC were identified through UPLC-MS/MS. An orthotopic transplantation model of CC was established in BALB/c mice using the CT26-Lucifer cell line, and the effects of AC were evaluated using IVIS imaging, hematoxylin and eosin (H&E) staining, and immunohistochemistry. Network pharmacology and molecular biology analyses were employed to identify the potential direct targets of AC. Subsequently, RT-PCR and Western blotting techniques were utilized to validate the findings obtained from network pharmacology. Furthermore, ELISA and other methodologies were used to investigate glycolysis-related indicators, along with immunofluorescence technology to demonstrate changes in vascular leakage and perfusion characteristics associated with blood vessel normalization.

Results

We identified HIF-1α as a potential direct target of AC. This interaction influences the glycolytic processes in both tumor cells and tumor-associated endothelial cells (TECs) by directly binding to HIF-1α and modulating its nuclear translocation, thereby determining the integrity of TEC junctions. Mechanistically, AC directly regulates the key enzyme PFKFB3 in glycolysis by modulating HIF-1α expression and inhibiting its nuclear translocation. This action reduces tumor glycolytic flux, decreases the internalization of VE-cad, and influences the expression of downstream matrix metalloproteinases (MMPs), thereby strengthening the adherens and tight junctions between TECs and restoring vascular integrity.

Conclusion

This study presents novel findings that AC can regulate glycolysis through the inhibition of HIF-1α nuclear translocation, thereby promoting the normalization of tumor blood vessels and effectively inhibiting tumor metastasis. These results suggested that AC may serve as an effective therapeutic agent for normalizing tumor blood vessels.