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

J Control Release. 2013 Oct 28;171(2):251-7. doi: 10.1016/j.jconrel.2013.07.017. Epub 2013 Jul 27.

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.

Keywords: Apoptosis; Cancer; Cathepsin D inhibitors; Cell penetrating compounds; Pepstatin bioconjugate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / 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
  • Dipeptides / pharmacology
  • Dipeptides / therapeutic use*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Pepstatins / chemistry
  • Pepstatins / pharmacology
  • Pepstatins / therapeutic use*
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

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