title: 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.affiliation: Institut des Biomolécules Max Mousseron (IBMM), UMR5247 CNRS Universités Montpellier 1 et 2, 15 Avenue Charles Flahault, 34000 Montpellier, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Maynadier
authors.forename: Lubomir L
authors.initials: LL
authors.lastname: Vezenkov
authors.forename: Muriel
authors.initials: M
authors.lastname: Amblard
authors.forename: Vincent
authors.initials: V
authors.lastname: Martin
authors.forename: Céline
authors.initials: C
authors.lastname: Gandreuil
authors.forename: Ophélie
authors.initials: O
authors.lastname: Vaillant
authors.forename: Magali
authors.initials: M
authors.lastname: Gary-Bobo
authors.forename: Ilaria
authors.initials: I
authors.lastname: Basile
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Hernandez
authors.forename: Marcel
authors.initials: M
authors.lastname: Garcia
authors.forename: Jean
authors.initials: J
authors.lastname: Martinez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010436:Pepstatins / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; C587693:JMV4463; D010436:Pepstatins; D053453:Caspase 9; D002402:Cathepsin D; C031375:pepstatin
keywords: Apoptosis; Cancer; Cathepsin D inhibitors; Cell penetrating compounds; Pepstatin bioconjugate