Dipeptide mimic oligomer transporter mediates intracellular delivery of Cathepsin D inhibitors: a potential target for cancer therapy.

Abstract

Implication of the intracellular proteolytic activity of Cathepsin D (CathD), a lysosomal aspartyl-protease overexpressed in numerous solid tumors, has been evidenced on tumor growth. Its intracellular inhibition by potent inhibitors such as pepstatin constitutes a relevant but challenging molecular target. Indeed the potential of pepstatin as a therapeutic molecule is hampered by its too low intracellular penetration. We addressed this limitation by designing and developing a bioconjugate combining a pepstatin derivative with a new vector of cell penetration (CPNP) specifically targeting the endolysosomal compartment. We showed that this pepstatin conjugate (JMV4463) exhibited high anti-proliferative effect on tumor cell cultures via intracellular CathD inhibition and altered cell cycle associated with apoptotic events in vitro. When tested in mice xenografted with breast cancer cells, JMV4463 delayed tumor emergence and growth.

• Authors: Marie Maynadier, Lubomir L Vezenkov, Muriel Amblard, Vincent Martin, Céline Gandreuil, Ophélie Vaillant, Magali Gary-Bobo, Ilaria Basile, Jean-François Hernandez, Marcel Garcia, Jean Martinez
• Journal: Journal of controlled release : official journal of the Controlled Release Society (J Control Release) Vol. 171 Issue 2 Pg. 251-7 (Oct 28 2013) ISSN: 1873-4995 [Electronic] Netherlands
• PMID: 23899821 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Antineoplastic Agents
• Dipeptides
• JMV4463
• Pepstatins
• Caspase 9
• Cathepsin D
• pepstatin

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Biological Transport (drug effects)
• Caspase 9 (metabolism)
• Cathepsin D (antagonists & inhibitors)
• Cell Cycle (drug effects)
• Cell Line, Tumor
• Dipeptides (chemistry, pharmacology, therapeutic use)
• Female
• Humans
• Mice
• Mice, Nude
• Neoplasms (drug therapy, metabolism, pathology)
• Pepstatins (chemistry, pharmacology, therapeutic use)
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays