Cytoxicity and Mode of Action of Aeroplysinin-1 and a Related Dienone from the Sponge Aplysina aerophoba

Abstract

Aeroplysinin-1 (1) and the structurally related dienone 2 were cytotoxic to Ehrlich ascites tumor (EAT) cells and HeLa tumor cells in the microculture tetrazolium (MTT) and clonogenic assays. Both compounds are bromotyrosine derivatives, isolated from the marine spong Aplysina aerophoba. As the effective concentrations in the MTT assay were lower than in the clonogenic assay, 1 and 2 are able to cause growth inhibition as well as actual cell death in these cell lines. With an IC50 value of 8.2 microM (MTT assay, 2-h incubation, EAT cells), 1 was the more toxic compound. When the cells were depleted of glutathione by pretreatment with buthionine sulfoximine, they were significantly more sensitive toward 1 and 2 in the MTT assay. A dose-enhancement factor as high as 11.8 was found in EAT cells after 2-h incubation with 2. Using electron paramagnetic resonance we were able to measure free radical formation of 1 and 2, yielding the semiquinone structures 3 and 4, respectively, in a culture medium with tumor cells. It is concluded that free radicals are, at least in part, responsible for the cytotoxicity of 1 and 2. This conclusion is in line with expectations derived from the chemical structures of both compounds.

The Marine Bromotyrosine Derivatives

“…In other studies, aeroplysinin-1 (14) and the related dienone 1 exhibited cytotoxicity against Ehrlich ascites tumor (EAT) cells and HeLa tumor cells in the microculture tetrazolium (MTT) and clonogenic assays (276). Both alkaloids were able to cause growth inhibition, as well as cell death, in these cell lines.…”

“…The structures of the geodiamolides were determined by 1D and 2D NMR spectroscopy, and the absolute stereochemistries of geodiamolides A (260) and H (267) were determined by Xray crystallography (158,161 263, 266, 267, 273, 276, 278, 270), bromine (261, 264, 268, 271, 274, 277 (263)(264)(265), and serine (276,277). The jaspamide/geodiamolide family of metabolites occurs across a taxonomically distant group of sponge species (156,(158)(159)(160)162,163).…”

“…Aeroplysinin-1 will generate free radicals after metabolic activation by the predator's cell, which results in an antifeedant effect. Simultaneously, the dienone 1 is released, which immediately yields free radicals in the water surrounding the sponge, thereby shielding the sponge from further predation or attack (276).…”

(+)-Aeroplysinin-1 inhibits Akt and Erk pathway signaling selectively in endothelial cells

“…The alkaloid compound aeroplysinin-1, synthesized by several marine sponges and secreted by them as a defensive weapon [1,4,5], exhibit cytostatic and cytotoxic effects on a wide range of both prokaryote and eukaryote cells [1,[4][5][6][7][8][9][10][11]14,17]. A suggested molecular target for the anti-tumor effect of aeroplysinin-1 is the EGFR tyrosine kinase activity.…”

“…The antibiotic action of aeroplysinin-1 makes it a potent antibacterial [1,4,5] and antiparasitic compound [6]. Furthermore, aeroplysinin-1 exhibits both cytostatic and cytotoxic effects on a wide range of tumor cells [7][8][9][10][11]. In particular, aeroplysinin-1 displays a potent anti-tumor effect on two human EGFdependent breast cancer cell lines through its claimed inhibitory effect on EGF-receptor tyrosine kinase activity [8].…”