Journal
JOURNAL OF CONTROLLED RELEASE
Volume 171, Issue 2, Pages 251-257Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jconrel.2013.07.017
Keywords
Cathepsin D inhibitors; Pepstatin bioconjugate; Cell penetrating compounds; Cancer; Apoptosis
Funding
- French National Agency (ANR) [ANR-08-BLAN-0066-01]
- ARC [3953]
- Agence Nationale de la Recherche (ANR) [ANR-08-BLAN-0066] Funding Source: Agence Nationale de la Recherche (ANR)
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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. (C) 2013 Elsevier B. V. All rights reserved.
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