Oncotarget

Research Papers:

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

María Roel _, Juan A. Rubiolo, Jorge Guerra-Varela, Siguara B. L. Silva, Olivier P. Thomas, Pablo Cabezas-Sainz, Laura Sánchez, Rafael López and Luis M. Botana

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Oncotarget. 2016; 7:83071-83087. https://doi.org/10.18632/oncotarget.13068

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Abstract

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

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.


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