The Natural Cell-Penetrating Peptide Crotamine Targets Tumor Tissue in Vivo and Triggers a Lethal Calcium-Dependent Pathway in Cultured Cells

• DOI: 10.1021/mp2000605
• Publication Date: 2011-12-05T15:12:54Z
• Authors: Fabio D. Nascimento; Lucie Sancey; Alexandre Pereira; Claire Rome; Vitor Oliveira; Eduardo B. Oliveira; Helena B. Nader; Tetsuo Yamane; Irina Kerkis; Ivarne L.S. Tersa...; Jean-Luc Coll; Mirian A.F. Hayashi
• Keywords: Thapsigargin; Calcium in biology; Membrane Potential, Mitochondrial; Cell Death; Cell Survival; Crotalus; Antineoplastic Agents; Cell-Penetrating Peptides; Lysosomes

Our goal was to demonstrate the in vivo tumor specific accumulation of crotamine, a natural peptide from venom South American rattlesnake Crotalus durissus terrificus, which has been characterized by our group as cell penetrating with high specificity for actively proliferating cells and concentration-dependent cytotoxic effect. Crotamine cytotoxicity shown be dependent on disruption lysosomes subsequent activation intracellular proteases. In this work, we show that effect crotamine also involves rapid calcium release loss mitochondrial membrane potential observed real time confocal microscopy. The overload induced almost completely blocked thapsigargin. Microfluorimetry assays confirmed importance internal organelles, such endoplasmic reticulum, contributors increase, well extracellular medium. Finally, here injected intraperitoneally can efficiently target remote subcutaneous tumors engrafted nude mice, demonstrated noninvasive optical imaging procedure permits real-time monitoring uptake into tissue. Taken together, data indicate used potentially dual purpose: detect growing tissues selectively trigger death.