title: Bcl-2 is a better ABT-737 target than Bcl-xL or Bcl-w and only Noxa overcomes resistance mediated by Mcl-1, Bfl-1, or Bcl-B.
abstract: The novel anticancer drug ABT-737 is a Bcl-2 Homology 3 (BH3)-mimetic that induces apoptosis by inhibiting pro-survival Bcl-2 proteins. ABT-737 binds with equal affinity to Bcl-2, Bcl-xL and Bcl-w in vitro and is expected to overrule apoptosis resistance mediated by these Bcl-2 proteins in equal measure. We have profiled ABT-737 specificity for all six pro-survival Bcl-2 proteins, in p53 wild-type or p53-mutant human T-leukemic cells. Bcl-B was untargeted, like Bfl-1 and Mcl-1, in accord with their low affinity for ABT-737 in vitro. However, Bcl-2 proved a better ABT-737 target than Bcl-xL and Bcl-w. This was reflected in differential apoptosis-sensitivity to ABT-737 alone, or combined with etoposide. ABT-737 was not equally effective in displacing BH3-only proteins or Bax from Bcl-2, as compared with Bcl-xL or Bcl-w, offering an explanation for the differential ABT-737 sensitivity of tumor cells overexpressing these proteins. Inducible expression demonstrated that BH3-only proteins Noxa, but not Bim, Puma or truncated Bid could overrule ABT-737 resistance conferred by Bcl-B, Bfl-1 or Mcl-1. These data identify Bcl-B, Bfl-1 and Mcl-1, but also Bcl-xL and Bcl-w as potential mediators of ABT-737 resistance and indicate that target proteins can be differentially sensitive to BH3-mimetics, depending on the pro-apoptotic Bcl-2 proteins they are complexed with.
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
authors.forename: R W
authors.initials: RW
authors.lastname: Rooswinkel
authors.forename: B
authors.initials: B
authors.lastname: van de Kooij
authors.forename: M
authors.initials: M
authors.lastname: Verheij
authors.forename: J
authors.initials: J
authors.lastname: Borst
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C501332:ABT-737; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C117144:BCL2-like 10 protein; C096816:BCL2-related protein A1; C491073:BCL2L2 protein, human; D001713:Biphenyl Compounds; D001897:Boronic Acids; D015778:Minor Histocompatibility Antigens; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D051020:bcl-X Protein; D000069286:Bortezomib; D005047:Etoposide