title: Specific targeting of caspase-9/PP2A interaction as potential new anti-cancer therapy.
abstract: OBJECTIVE
  PP2A is a serine/threonine phosphatase critical to physiological processes, including apoptosis. Cell penetrating peptides are molecules that can translocate into cells without causing membrane damage. Our goal was to develop cell-penetrating fusion peptides specifically designed to disrupt the caspase-9/PP2A interaction and evaluate their therapeutic potential in vitro and in vivo.
  
  
  METHODS
  We generated a peptide containing a penetrating sequence associated to the interaction motif between human caspase-9 and PP2A (DPT-C9h), in order to target their association. Using tumour cell lines, primary human cells and primary human breast cancer (BC) xenografts, we investigated the capacity of DPT-C9h to provoke apoptosis in vitro and inhibition of tumour growth (TGI) in vivo. DPT-C9h was intraperitoneally administered at doses from 1 to 25 mg/kg/day for 5 weeks. Relative Tumour Volume (RTV) was calculated.
  
  
  RESULTS
  We demonstrated that DPT-C9h specifically target caspase-9/PP2A interaction in vitro and in vivo and induced caspase-9-dependent apoptosis in cancer cell lines. DPT-C9h also induced significant TGI in BC xenografts models. The mouse-specific peptide DPT-C9 also induced TGI in lung (K-Ras model) and breast cancer (PyMT) models. DPT-C9h has a specific effect on transformed B cells isolated from chronic lymphocytic leukemia patients without any effect on primary healthy cells. Finally, neither toxicity nor immunogenic responses were observed.
  
  
  CONCLUSIONS
  Using the cell-penetrating peptides blocking caspase-9/PP2A interactions, we have demonstrated that DPT-C9h had a strong therapeutic effect in vitro and in vivo in mouse models of tumour progression.
authors: Inserm UMRS 945, Hôpital Pitié Salpêtrière, Université Pierre et Marie Curie, Paris, France.
authors: Issam
authors: I
authors: Arrouss
authors: Fariba
authors: F
authors: Nemati
authors: Fernando
authors: F
authors: Roncal
authors: Marie
authors: M
authors: Wislez
authors: Karim
authors: K
authors: Dorgham
authors: David
authors: D
authors: Vallerand
authors: Nathalie
authors: N
authors: Rabbe
authors: Narjesse
authors: N
authors: Karboul
authors: Françoise
authors: F
authors: Carlotti
authors: Jeronimo
authors: J
authors: Bravo
authors: Dominique
authors: D
authors: Mazier
authors: Didier
authors: D
authors: Decaudin
authors: Angelita
authors: A
authors: Rebollo
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001665:Binding Sites; D001943:Breast Neoplasms / Q000188:drug therapy; D053453:Caspase 9 / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D045304:Cytochromes c / Q000378:metabolism; D015195:Drug Design; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D011485:Protein Binding / Q000187:drug effects; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism*; D013045:Species Specificity; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D057846:Cell-Penetrating Peptides; D045304:Cytochromes c; D054648:Protein Phosphatase 2; D053453:Caspase 9
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