Coibamide A, a natural lariat depsipeptide, inhibits VEGFA/VEGFR2 expression and suppresses tumor growth in glioblastoma xenografts
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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.
KeywordsCoibamide A Apratoxin A Cyclic depsipeptide Antiangiogenic Autophagy Glioblastoma
We thank the Autoridad Nacional del Ambiente (ANAM), Panama for permission to make recollections (in 2012) of the coibamide A-producing cyanobacterium and funding from the NIH Fogarty International Center ICBG grant TW006634-06 (KLM) for collection and isolation. We also thank the Red Sea Protectorate for permission to make collections of the apratoxin-producing cyanobacterium (in 2007). This work was supported by an American Brain Tumor Association (ABTA) Discovery Grant (to JEI) and funding from the Oregon State University (OSU) General Research Fund. We are also grateful for the core facilities of the OSU Environmental Heath Sciences Center (P30-ES000210) and support from the American Foundation for Pharmaceutical Education (AFPE) in the form of an AFPE Pre-Doctoral Fellowship in the Pharmaceutical Sciences to JDS.
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Conflict of interest
The authors declare they have no conflict of interest.
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