crambescidin-800 and Colorectal-Neoplasms

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.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Caspase 3; Cell Adhesion; Cell Cycle Proteins; Cell Proliferation; Cell Survival; Colorectal Neoplasms; Cytoskeleton; Dose-Response Relationship, Drug; G1 Phase Cell Cycle Checkpoints; Guanidine; Hep G2 Cells; HT29 Cells; Humans; Inhibitory Concentration 50; MCF-7 Cells; Membrane Potential, Mitochondrial; Signal Transduction; Spiro Compounds; Time Factors; Tumor Burden; Xenograft Model Antitumor Assays; Zebrafish