Apratoxin S10, a Dual Inhibitor of Angiogenesis and Cancer Cell Growth To Treat Highly Vascularized Tumors

Abstract

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.

Apratoxin S4 Inspired by a Marine Natural Product, a New Treatment Option for Ocular Angiogenic Diseases

“…Apratoxins were previously reported to exert its function by inhibiting protein co-translational translocation at the level of Sec61 translocon, leading to downregulation of various receptor tyrosine kinases and growth factors. 13,14,[16][17][18]36 Consistent with these observations [20], receptor tyrosine kinase VEGFR2 and VEGFR3 expressions were significantly inhibited in Apratoxin S4-treated HRECs. Similarly, receptor tyrosine kinase PDGFR-b level in HRPCs was also suppressed by Apratoxin S4.…”

“…Natural and synthetic Apratoxins are potent antitumor and antiangiogenic macrocyclic depsipeptides derived from marine cyanobacteria. [16][17][18]35,36 It was reported that Apratoxins exert their function through inhibiting co-translational translocation of secreted or membrane bound proteins, 13 which may offer an alternative way to control the activation of angiogenic pathways.…”

“…Consistent with the previously reported role of natural and novel synthetic Apratoxins in human umbilical vein endothelial cells (HUVECs). 18,35 Apratoxin S4 potently inhibits HREC proliferation and migration, and the ability of HRECs to form tube-like structures. Interestingly, the VEGF-activated HRECs are more susceptible to the treatment of Apratoxin S4, which offers a selectivity advantage for Apratoxin S4 on angiogenic processes over quiescent vasculature.…”

“…Natural and synthetic Apratoxins were previously reported to control co-translational translocation of a number of receptor tyrosine kinases, including VEGFR2. 13,18 To further understand the mechanism of action of synthetic Apratoxin S4, we evaluated the expression of key angiogenic regulators, their receptors, and downstream signaling transducers in Apratoxin S4-treated HRECs with aflibercept used as a control. Whereas the expression level of VEGFR1 remained unchanged, VEGFR2 and VEGFR3 levels in HRECs were significantly suppressed by 25 nM Apratoxin S4, which was associated with a concomitant reduction in level of its activated downstream signaling transducer, pErk1/2 (Fig.…”

“…16,17 The dual effect of synthetic Apratoxin S4 on membrane receptors and their ligands, including VEGFR2 and VEGF, promises to be effective against tumors that rely on autocrine loops 16 and to effectively control vascularized tumors by targeting both cancer cell growth and angiogenesis. 18 Considering the benefits of synthetic Apratoxins in tumor angiogenesis, we intended to explore the impact of Apratoxin S4 on ocular-specific vascular cell activation and angiogenesis.…”