Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model
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María Roel1, Juan A. Rubiolo1, Jorge Guerra-Varela2, Siguara B. L. Silva3,4, Olivier P. Thomas3,5, Pablo Cabezas-Sainz2, Laura Sánchez2, Rafael López6, Luis M. Botana1
1Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain
2Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain
3Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA, 06560 Valbonne, France
4Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 92290 Châtenay-Malabry, France
5School of Chemistry, Marine Biodiscovery, National University of Ireland Galway, SW4 Galway, Ireland
6Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain
Luis M. Botana, email: [email protected]
Keywords: crambescidins, cell cycle inhibition, apoptosis, zebrafish xenograft model, cancer treatment
Received: March 13, 2016 Accepted: September 27, 2016 Published: November 04, 2016
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.
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