Natural products from both terrestrial and marine sources represent a significant source of novel drug leads, and have previously been developed into clinically-approved agents for the treatment of various human diseases. This work represents the biological characterization of the mechanistic basis for activity of several natural product structures in models of glioblastoma multiforme (GBM), in an effort to assess their potential utility with regard to future therapeutic contexts. Apoptolidins A and C are macrolide secondary metabolites produced by an actinomycete isolated from Indonesian soil samples. We show that these structures inhibit mitochondrial F0F1 ATP synthase and activate the AMPK energy stress signaling pathway in cells; downstream of this activation, autophagic flux is triggered in an mTOR-independent manner. Coibamide A is a depsipeptide natural product structure isolated from a Panamanian cyanobacterial assemblage. We show that the structure inhibits in vitro invasive and migratory behavior in glioma cells, and also tumor growth in a murine xenograft model of human glioblastoma. Coibamide A inhibits the expression of vascular endothelial growth factor (VEGF) and mature VEGF receptor 2 (VEGFR2) in different cell types, and inhibits the proliferation, migratory behavior, and three-dimensional network formation of primary umbilical vein endothelial cells (HUVECs) in vitro. We show that the mechanistic basis for these effects can be attributed to the structure's ability to inhibit the mammalian secretory pathway, as evidenced by inhibition of the mature form of overexpressed VCAM-1 protein in HEK-293 cells, disruption of Gaussia Luciferase secretion in lentiviral-infected glioblastoma cells, and inhibition of glycosylation activity in an in vitro translation assay.