title: Forodesine has high antitumor activity in chronic lymphocytic leukemia and activates p53-independent mitochondrial apoptosis by induction of p73 and BIM.
abstract: Chronic lymphocytic leukemia (CLL) is an incurable disease derived from the monoclonal expansion of CD5(+) B lymphocytes. High expression levels of ZAP-70 or CD38 and deletions of 17p13 (TP53) and 11q22-q23 (ATM) are associated with poorer overall survival and shorter time to disease progression. DNA damage and p53 play a pivotal role in apoptosis induction in response to conventional chemotherapy, because deletions of ATM or p53 identify CLL patients with resistance to treatment. Forodesine is a transition-state inhibitor of the purine nucleoside phosphorylase with antileukemic activity. We show that forodesine is highly cytotoxic as single agent or in combination with bendamustine and rituximab in primary leukemic cells from CLL patients regardless of CD38/ZAP-70 expression and p53 or ATM deletion. Forodesine activates the mitochondrial apoptotic pathway by decreasing the levels of antiapoptotic MCL-1 protein and induction of proapoptotic BIM protein. Forodesine induces transcriptional up-regulation of p73, a p53-related protein able to overcome the resistance to apoptosis of CLL cells lacking functional p53. Remarkably, no differences in these apoptotic markers were observed based on p53 or ATM status. In conclusion, forodesine induces apoptosis of CLL cells bypassing the DNA-damage/ATM/p53 pathway and might represent a novel chemotherapeutic approach that deserves clinical investigation.
authors.affiliation: Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Alonso
authors.forename: Mónica
authors.initials: M
authors.lastname: López-Guerra
authors.forename: Ramanda
authors.initials: R
authors.lastname: Upshaw
authors.forename: Shanta
authors.initials: S
authors.lastname: Bantia
authors.forename: Caroline
authors.initials: C
authors.lastname: Smal
authors.forename: Françoise
authors.initials: F
authors.lastname: Bontemps
authors.forename: Chantal
authors.initials: C
authors.lastname: Manz
authors.forename: Thomas
authors.initials: T
authors.lastname: Mehrling
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.forename: Elias
authors.initials: E
authors.lastname: Campo
authors.forename: Emili
authors.initials: E
authors.lastname: Montserrat
authors.forename: Dolors
authors.initials: D
authors.lastname: Colomer
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D000069461:Bendamustine Hydrochloride; D003520:Cyclophosphamide / Q000008:administration & dosage; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011684:Purine Nucleosides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011744:Pyrimidinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000069283:Rituximab; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism; D014740:Vidarabine / Q000008:administration & dosage / Q000031:analogs & derivatives
chemical_list: D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D009588:Nitrogen Mustard Compounds; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D011684:Purine Nucleosides; D011744:Pyrimidinones; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C113101:forodesine; D000069283:Rituximab; D003520:Cyclophosphamide; D000069461:Bendamustine Hydrochloride; D014740:Vidarabine; C024352:fludarabine