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

Jeffrey D. Serrill, Xuemei Wan, Andrew M. Hau, Hyo Sang Jang, Daniel J. Coleman, Arup K. Indra, Adam W.G. Alani, Kerry L. McPhail, Jane E. Ishmael

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

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 G1 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.

Original languageEnglish (US)
Pages (from-to)24-40
Number of pages17
JournalInvestigational New Drugs
Volume34
Issue number1
DOIs
StatePublished - Feb 1 2016
Externally publishedYes

Keywords

  • Antiangiogenic
  • Apratoxin A
  • Autophagy
  • Coibamide A
  • Cyclic depsipeptide
  • Glioblastoma

ASJC Scopus subject areas

  • Oncology
  • Pharmacology
  • Pharmacology (medical)

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