The oncolytic peptide LTX-315 triggers necrotic cell death.

Abstract

The oncolytic peptide LTX-315 has been designed for killing human cancer cells and turned out to stimulate anti-cancer immune responses when locally injected into tumors established in immunocompetent mice. Here, we investigated the question whether LTX-315 induces apoptosis or necrosis. Transmission electron microscopy or morphometric analysis of chromatin-stained tumor cells revealed that LTX-315 failed to induce apoptotic nuclear condensation and rather induced a necrotic phenotype. Accordingly, LTX-315 failed to stimulate the activation of caspase-3, and inhibition of caspases by means of Z-VAD-fmk was unable to reduce cell killing by LTX-315. In addition, 2 prominent inhibitors of regulated necrosis (necroptosis), namely, necrostatin-1 and cycosporin A, failed to reduce LTX-315-induced cell death. In conclusion, it appears that LTX-315 triggers unregulated necrosis, which may contribute to its pro-inflammatory and pro-immune effects.

• Authors: Sabrina Forveille, Heng Zhou, Allan Sauvat, Lucillia Bezu, Kevin Müller, Peng Liu, Laurence Zitvogel, Gérard Pierron, Øystein Rekdal, Oliver Kepp, Guido Kroemer
• Journal: Cell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 14 Issue 21 Pg. 3506-12 ( 2015) ISSN: 1551-4005 [Electronic] United States
• PMID: 26566869 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amino Acid Chloromethyl Ketones
• Antineoplastic Agents
• Caspase Inhibitors
• Imidazoles
• Indoles
• LTX-315
• Oligopeptides
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• necrostatin-1
• Cyclosporine

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Bone Neoplasms (drug therapy, metabolism, ultrastructure)
• Caspase Inhibitors (pharmacology)
• Cell Line, Tumor
• Cyclosporine (pharmacology)
• Dose-Response Relationship, Drug
• Humans
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Microscopy, Electron, Transmission
• Necrosis
• Oligopeptides (pharmacology)
• Osteosarcoma (drug therapy, metabolism, ultrastructure)
• Time Factors