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.