Marine guanidine alkaloids crambescidins inhibit tumor growth and activate intrinsic apoptotic signaling inducing tumor regression in a colorectal carcinoma zebrafish xenograft model.
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.
Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
María
M
Roel
Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
Juan A
JA
Rubiolo
Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
Jorge
J
Guerra-Varela
Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA, 06560 Valbonne, France.|Laboratoire de Pharmacognosie, UMR CNRS 8076 BioCIS, LabEx LERMIT, Université Paris-Sud, Faculté de Pharmacie, 92290 Châtenay-Malabry, France.
Siguara B L
SB
Silva
Geoazur, UMR Université Nice Sophia Antipolis-CNRS-IRD-OCA, 06560 Valbonne, France.|School of Chemistry, Marine Biodiscovery, National University of Ireland Galway, SW4 Galway, Ireland.
Olivier P
OP
Thomas
Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
Pablo
P
Cabezas-Sainz
Department of Genetics, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
Laura
L
Sánchez
Translational Medical Oncology, Health Research Institute of Santiago (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (SERGAS), 15706 Santiago de Compostela, Spain.
Rafael
R
López
Department of Pharmacology, Universidade de Santiago de Compostela, Campus Lugo, 27002 Lugo, Spain.
Luis M
LM
Botana
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D019791:Guanidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019073:HT29 Cells; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013141:Spiro Compounds / Q000494:pharmacology*; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish
D000470:Alkaloids; D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D013141:Spiro Compounds; C490355:crambescidin 800; C083155:crambescidin 816; C505407:CASP3 protein, human; D053148:Caspase 3; D019791:Guanidine
apoptosis; cancer treatment; cell cycle inhibition; crambescidins; zebrafish xenograft model