Renal, hepatocellular, and neuroendocrine carcinomas are known as highly vascularized tumors. Although vascular endothelial growth factor A (VEGF-A)-targeted therapies have shown efficacy in the treatment of these cancers, drug resistance is a major concern and might be mediated by interleukin 6 (IL-6). Furthermore, upon antiangiogenic drug exposure, tumor cells may adapt to survive in a vascular-independent manner. Apratoxins are potent marine-derived cytotoxic in vivo-active agents, preventing cotranslational translocation in the secretory pathway, and show promise to overcome resistance by targeting angiogenesis and tumor growth simultaneously. We designed and synthesized a novel apratoxin analogue, apratoxin S10, with a balanced potency and stability as well as synthetic accessibility and scalability. We showed that apratoxin S10 potently inhibits both angiogenesis in vitro and growth of cancer cells from vascularized tumors. Apratoxin S10 down-regulated vascular endothelial growth factor receptor 2 (VEGFR2) on endothelial cells and blocked the secretion of VEGF-A and IL-6 from cancer cells. It inhibited cancer cell growth through down-regulation of multiple receptor tyrosine kinases (RTKs) and compares favorably to currently approved RTK inhibitors in both angiogenesis and cancer cell growth.

中文翻译：

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Apratoxin S10，血管生成和癌细胞生长的双重抑制剂，可治疗高度血管化的肿瘤

肾癌，肝细胞癌和神经内分泌癌被称为高度血管化的肿瘤。尽管以血管内皮生长因子A（VEGF-A）为目标的疗法已显示出可治疗这些癌症的功效，但耐药性仍是一个主要问题，可能由白介素6（IL-6）介导。此外，在抗血管生成药物暴露后，肿瘤细胞可以适应血管依赖性生存。Apratoxins是有效的海洋来源的细胞毒性体内活性剂，可防止分泌途径中的共翻译易位，并有望通过同时靶向血管生成和肿瘤生长来克服耐药性。我们设计并合成了一种新型的人毒素毒素类似物，人毒素毒素S10，具有平衡的效价和稳定性以及合成的可及性和可扩展性。我们表明，Apratoxin S10有效抑制体外血管生成和血管瘤中癌细胞的生长。Apratoxin S10下调了内皮细胞上的血管内皮生长因子受体2（VEGFR2），并阻止了癌细胞分泌VEGF-A和IL-6。它通过下调多种受体酪氨酸激酶（RTK）抑制癌细胞的生长，在血管生成和癌细胞生长方面均优于目前批准的RTK抑制剂。