Abstract
The marine environment constitutes an extraordinary resource for the discovery of new therapeutic agents. In the present manuscript we studied the effect of 3 different sponge derived guanidine alkaloids, crambescidine-816, -830, and -800. We show that these compounds strongly inhibit tumor cell proliferation by down-regulating cyclin-dependent kinases 2/6 and cyclins D/A expression while up-regulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We also show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation. The crambescidin 816 anti-tumor effect was fnally assayed in a zebrafish xenotransplantation model confirming its potent antitumor activity against colorectal carcinoma in vivo.Considering these results crambescidins could represent promising natural anticancer agents and therapeutic tools.
Highlights
The increasing interest in screening for novel agents from marine organisms is supported by their ability to synthesize an arsenal of bioactive secondary metabolites with pharmacologically significant activities and unusual chemical structures, quite different from those produced by terrestrial ones [1]
We show that these compounds strongly inhibit tumor cell proliferation by downregulating cyclin-dependent kinases 2/6 and cyclins D/A expression while upregulating the cell cyclin-dependent kinase inhibitors -2A, -2D and -1A. We show that these guanidine compounds disrupt tumor cell adhesion and cytoskeletal integrity promoting the activation of the intrinsic apoptotic signaling, resulting in loss of mitochondrial membrane potential and concomitant caspase-3 cleavage and activation
While some previous studies revealed the cytotoxicity of crambescidin 816 (C816) against human colon carcinoma cells (IC50 0.24 μg/ml) [3] and others inquired the relationship between tumor selectivity and crambescidin alkaloids analogs structures [10], the understanding of the underlying cellular mechanisms responsible for their antitumor activities is scarce up to date
Summary
The increasing interest in screening for novel agents from marine organisms is supported by their ability to synthesize an arsenal of bioactive secondary metabolites with pharmacologically significant activities and unusual chemical structures, quite different from those produced by terrestrial ones [1]. While some previous studies revealed the cytotoxicity of C816 against human colon carcinoma cells (IC50 0.24 μg/ml) [3] and others inquired the relationship between tumor selectivity and crambescidin alkaloids analogs structures [10], the understanding of the underlying cellular mechanisms responsible for their antitumor activities is scarce up to date In this context, we previously assayed the transcriptomic alterations induced by C816 on the human liver carcinoma cell line HepG2 showing that this compound arrests cell cycle progression disrupting cell-cell and cell-matrix adhesions [11]. The growing interest of both, adult and embryo stage zebrafish, in pharmacology is supported by several hallmarks of this small vertebrate as its fecundity, fast development, big offspring size, transparency, high genetic and physiological homology to humans and theease of genetic manipulation These characteristics provide important utilities and opportunities to accelerate the process of drug discovery by contributing to disease modeling, assay of toxicity, bioavailability evaluation and lead molecules identification. Zebrafish xenografts have been widely used before as reliable whole-animal model systems to rapidly screen for small-molecule drug candidates [15,16,17]
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