Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts

• Published in: Investigational new drugs Vol. 34; no. 1; pp. 24 - 40
• Main Authors: Serrill, Jeffrey D., Wan, Xuemei, Hau, Andrew M., Jang, Hyo Sang, Coleman, Daniel J., Indra, Arup K., Alani, Adam W. G., McPhail, Kerry L., Ishmael, Jane E.
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2016; Springer Nature B.V
• Subjects: Animals; Antibodies; Antineoplastic Agents - pharmacology; Apoptosis; Autophagy; Biodiversity; Breast cancer; Breast Neoplasms - drug therapy; Breast Neoplasms - pathology; Cancer; Cell cycle; Cell death; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Chemistry; Chemotherapy; Cytotoxicity; Depsipeptides - pharmacology; Drugs; FDA approval; Female; Glioblastoma - drug therapy; Glioblastoma - pathology; Human Umbilical Vein Endothelial Cells; Humans; Laboratories; Medicine; Medicine & Public Health; Mice; Mice, Nude; National parks; Natural products; Oncology; Pharmaceutical sciences; Pharmaceuticals; Pharmacology/Toxicology; Preclinical Studies; Prescription drugs; R&D; Research & development; Studies; Toxicity; Tumors; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor Receptor-2 - antagonists & inhibitors; Xenograft Model Antitumor Assays; Coibamide A; Apratoxin A; Cyclic depsipeptide; Antiangiogenic; Autophagy; Glioblastoma
• ISSN: 0167-6997; 1573-0646
• DOI: 10.1007/s10637-015-0303-x

Summary Coibamide A is a cytotoxic lariat depsipeptide isolated from a rare cyanobacterium found within the marine reserve of Coiba National Park, Panama. Earlier testing of coibamide A in the National Cancer Institute in vitro 60 human tumor cell line panel (NCI-60) revealed potent anti-proliferative activity and a unique selectivity profile, potentially reflecting a new target or mechanism of action. In the present study we evaluated the antitumor activity of coibamide A in several functional cell-based assays and in vivo. U87-MG and SF-295 glioblastoma cells showed reduced migratory and invasive capacity and underwent G 1 cell cycle arrest as, likely indirect, consequences of treatment . Coibamide A inhibited extracellular VEGFA secreted from U87-MG glioblastoma and MDA-MB-231 breast cancer cells with low nM potency, attenuated proliferation and migration of normal human umbilical vein endothelial cells (HUVECs) and selectively decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2). We report that coibamide A retains potent antitumor properties in a nude mouse xenograft model of glioblastoma; established subcutaneous U87-MG tumors failed to grow for up to 28 days in response to 0.3 mg/Kg doses of coibamide A. However, the natural product was also associated with varied patterns of weight loss and thus targeted delivery and/or medicinal chemistry approaches will almost certainly be required to improve the toxicity profile of this unusual macrocycle. Finally, similarities between coibamide A- and apratoxin A-induced changes in cell morphology, decreases in VEGFR2 expression and macroautophagy signaling in HUVECs raise the possibility that both cyanobacterial natural products share a common mechanism of action.