Metformin and simvastatin synergistically suppress endothelin 1‐induced hypoxia and angiogenesis in multiple cancer types

Abstract

Multiple cancers have been reported to be associated with angiogenesis and are sensitive to anti‐angiogenic therapies. Vascular normalization, by restoring proper tumor perfusion and oxygenation, could limit tumor cell invasiveness and improve the effectiveness of anticancer treatments. However, the underlying anticancer mechanisms of antiangiogenic drugs are still unknown. Metformin (MET) and simvastatin (SVA), two metabolic‐related drugs, have been shown to play important roles in modulating the hypoxic tumor microenvironment and angiogenesis. Whether the combination of MET and SVA could exert a more effective antitumor effect than individual treatments has not been examined. The antitumor effect of the synergism of SVA and MET was detected in mouse models, breast cancer patient‐derived organoids, and multiple tumor cell lines compared with untreated, SVA, or MET alone. RNA sequencing revealed that the combination of MET and SVA (but not MET or SVA alone) inhibited the expression of endothelin 1 (ET‐1), an important regulator of angiogenesis and the hypoxia‐related pathway. We demonstrate that the MET and SVA combination showed synergistic effects on inhibiting tumor cell proliferation, promoting apoptosis, alleviating hypoxia, decreasing angiogenesis, and increasing vessel normalization compared with the use of a single agent alone. The MET and SVA combination suppressed ET‐1‐induced hypoxia‐inducible factor 1α expression by increasing prolyl hydroxylase 2 (PHD2) expression. Furthermore, the MET and SVA combination showed a more potent anticancer effect compared with bosentan. Together, our findings suggest the potential application of the MET and SVA combination in antitumor therapy.

KLF2 is a clinical diagnostic and treatment biomarker of breast cancer

“…Based on our previous investigations, simvastatin has been shown to effectively inhibit the proliferation of tumor cells, including breast cancer and liver cancer cells, as well as impeding the growth of patient-derived organoids (PDOs), mammary and melanoma tumors in mice ( Li et al, 2017 ; Wang et al, 2018 ; Liu et al, 2023 ). Consequently, we analyzed the expression of KLF2 in mouse tumor tissue treated with simvastatin, which exhibited a significant increase compared to the control group ( Figures 9A, B ).…”

Endothelin and the tumor microenvironment: a finger in every pie

“…Recent research has shown that the combination of metformin and simvastatin inhibits tumor progression and attenuates hypoxia. Reduced expression of EDN1 in RNA sequencing and reduced HIF-1α levels point to the ET axis as the driving mechanism, but further studies are needed to conclusively demonstrate the causality of this relationship [ 49 ]. HIF-1α in a complex with yes-associated protein (YAP), mutant p53 and β-arrestin was also recently identified as an escape mechanism of high-grade serous ovarian carcinoma (HG-SOC) cells for poly-ADP-ribose polymerase (PARP) inhibition.…”

A Novel PTH‐Related Peptide Combined With 3D Printed Macroporous Titanium Alloy Scaffold Enhances Osteoporotic Osseointegration

“…[33,34] Targeted inhibition of ET-1 and its receptors can diminish the formation of tumor blood vessels. [35,36] Further investigations have revealed that ET-1 was located downstream of transforming growth factor 𝛽 (TGF-𝛽) during angiogenesis and vascular maturation, mediating the interaction between lysyl oxidase and TGF-𝛽. [37] Studies have demonstrated that ET-1 can enhance the regenerative capacity of human mesenchymal stem cells and promote the osteogenic differentiation of BMSCs by regulating the activation of protein kinase B and ERK1/2 signaling pathways.…”