Effective Suppression of Hypoxia Induced Angiogenesis by Synergism of Simvastatin and Metformin via Inhibiting ET-1-ETBR-Hif1α Signaling Axis

Abstract Background: Hypoxic stress accelerates metabolic reprogramming to promote malignant progression, which contains huge and interesting drug targets for cancer therapy. According to recently reports and our previously researches, simvastatin (SVA) or metformin (MET), two metabolic relevant drugs, play an important role in inhibiting tumor growth, angiogenesis, improvement hypoxic microenvironment. However, the signal networks of hypoxia induced metabolic reprogramming is enormous and intricacy, blocking a signal target can’t play an effective role in antitumor, whether combination of SVA and MET could exert a more effective antitumor effect is not clear.Methods: The antitumor effect of synergism of SVA and MET were detected in mouse models, breast cancer patient-derived organoid (PDO) and multiple tumor cell lines compared with untreated, SVA or MET alone. Transcriptome sequencing were performed for exploring the possible mechanisms. Inhibition of endothelin 1 (ET-1) induced Hif1α by synergism of SVA and MET were contrasted with bosentan, an ETBR antagonist.Results: Our results show that synergism of SVA and MET can inhibit tumor cell proliferation and promote apoptosis, alleviate hypoxia, decrease angiogenesis and increase vessel normalization within tumor than use of SVA or MET alone. RNA-sequencing result implies that just synergism of SVA and MET can inhibit EDN1 expression, which encodes endothelin 1, an important regulator of angiogenesis and hypoxia-related pathway, but not in use of SVA or MET alone. More specifically, synergism of SVA and MET suppresses the ET-1 induced Hif1α expression by inhibiting ET-1-ETBR signaling pathway and increasing PHD2 expression. In addition, the antitumor effect of synergism of SVA and MET is more efficient than bosentan in tumor cells and breast cancer PDO by inhibiting ET-1-ETBR-Hif1α signaling axis.Conclusions: Thus, our data show that synergism of SVA and MET can be a viable therapy for antitumor.