The Natural Cell-Penetrating Peptide Crotamine Targets Tumor Tissue in Vivo and Triggers a Lethal Calcium-Dependent Pathway in Cultured Cells
| Autor: | Eduardo B. Oliveira, Alexandre Pereira, Helena B. Nader, Jean-Luc Coll, Fabio D. Nascimento, Vitor Oliveira, Irina Kerkis, Mirian A. F. Hayashi, Lucie Sancey, Tetsuo Yamane, Ivarne L.S. Tersariol, Claire Rome |
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| Rok vydání: | 2011 |
| Předmět: |
Thapsigargin
Cell Survival Mice Nude Pharmaceutical Science Antineoplastic Agents CHO Cells Cell-Penetrating Peptides Mitochondrion Biology Endoplasmic Reticulum Calcium in biology Mice chemistry.chemical_compound Cricetulus Cricetinae Neoplasms Crotalid Venoms Drug Discovery Tumor Cells Cultured Extracellular Animals Humans Calcium Signaling Membrane Potential Mitochondrial Microscopy Confocal Cell Death Endoplasmic reticulum Crotalus Microfluorimetry Flow Cytometry Xenograft Model Antitumor Assays Cell biology Crotamine HEK293 Cells chemistry Molecular Medicine Calcium Lysosomes Injections Intraperitoneal Intracellular |
| Zdroj: | Molecular Pharmaceutics. 9:211-221 |
| ISSN: | 1543-8392 1543-8384 |
| DOI: | 10.1021/mp2000605 |
| Popis: | Our goal was to demonstrate the in vivo tumor specific accumulation of crotamine, a natural peptide from the venom of the South American rattlesnake Crotalus durissus terrificus, which has been characterized by our group as a cell penetrating peptide with a high specificity for actively proliferating cells and with a concentration-dependent cytotoxic effect. Crotamine cytotoxicity has been shown to be dependent on the disruption of lysosomes and subsequent activation of intracellular proteases. In this work, we show that the cytotoxic effect of crotamine also involves rapid intracellular calcium release and loss of mitochondrial membrane potential as observed in real time by confocal microscopy. The intracellular calcium overload induced by crotamine was almost completely blocked by thapsigargin. Microfluorimetry assays confirmed the importance of internal organelles, such as lysosomes and the endoplasmic reticulum, as contributors for the intracellular calcium increase, as well as the extracellular medium. Finally, we demonstrate here that crotamine injected intraperitoneally can efficiently target remote subcutaneous tumors engrafted in nude mice, as demonstrated by a noninvasive optical imaging procedure that permits in vivo real-time monitoring of crotamine uptake into tumor tissue. Taken together, our data indicate that the cytotoxic peptide crotamine can be used potentially for a dual purpose: to target and detect growing tumor tissues and to selectively trigger tumor cell death. |
| Databáze: | OpenAIRE |
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