Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model

// María Roel 1 , Juan A. Rubiolo 1 , Jorge Guerra-Varela 2 , Siguara B. L. Silva 3, 4 , Olivier P. Thomas 3, 5 , Pablo Cabezas-Sainz 2 , Laura Sánchez 2 , Rafael López 6 , Luis M. Botana 1 1 Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain 2 Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain 3 Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA, 06560 Valbonne, France 4 Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 92290 Châtenay-Malabry, France 5 School of Chemistry, Marine Biodiscovery, National University of Ireland Galway, SW4 Galway, Ireland 6 Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain Correspondence to: Luis M. Botana, email: luis.botana@usc.es Keywords: crambescidins, cell cycle inhibition, apoptosis, zebrafish xenograft model, cancer treatment Received: March 13, 2016      Accepted: September 27, 2016      Published: November 04, 2016 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.