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.

中文翻译：

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二甲双胍和辛伐他汀在多种癌症类型中协同抑制内皮素 1 诱导的缺氧和血管生成

据报道，多种癌症与血管生成有关，并且对抗血管生成疗法敏感。通过恢复适当的肿瘤灌注和氧合作用，血管正常化可以限制肿瘤细胞的侵袭并提高抗癌治疗的有效性。然而，抗血管生成药物的潜在抗癌机制仍然未知。二甲双胍 (MET) 和辛伐他汀 (SVA) 是两种代谢相关药物，已被证明在调节缺氧肿瘤微环境和血管生成中发挥重要作用。MET 和 SVA 的组合是否可以发挥比单独治疗更有效的抗肿瘤作用尚未得到检验。在小鼠模型、乳腺癌患者来源的类器官、和多个肿瘤细胞系与单独的未治疗、SVA 或 MET 相比。RNA 测序表明，MET 和 SVA 的组合（但不是单独的 MET 或 SVA）抑制了内皮素 1 (ET-1) 的表达，内皮素 1 (ET-1) 是血管生成和缺氧相关通路的重要调节因子。我们证明，与单独使用单一药物相比，MET 和 SVA 组合在抑制肿瘤细胞增殖、促进细胞凋亡、缓解缺氧、减少血管生成和增加血管正常化方面显示出协同作用。MET 和 SVA 组合通过增加脯氨酰羟化酶 2 (PHD2) 的表达来抑制 ET-1 诱导的缺氧诱导因子 1α 的表达。此外，与波生坦相比，MET 和 SVA 组合显示出更有效的抗癌作用。一起，