title: Promise of combining a Bcl-2 family inhibitor with bortezomib or SAHA for adult T-cell leukemia/lymphoma.
abstract: BACKGROUND
  Adult T-cell leukemia/lymphoma (ATL) is an aggressive malignancy of peripheral T-lymphocytes and its prognosis still remains very poor.
  
  
  METHODS
  The potential of combining the Bcl-2 homology 3 mimetic ABT-737, which blocks Bcl-2, Bcl-XL, and Bcl-w, with either the proteasome inhibitor bortezomib or histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA) to inhibit the growth of human T-lymphotropic virus type-I (HTLV-1) infected T-cell lines and its mechanism was further evaluated.
  
  
  RESULTS
  ABT-737 synergistically induced apoptosis when combined with either bortezomib or SAHA in HTLV-1 infected T-cell lines and fresh ATL cells. Bortezomib increased the expression of Noxa, which subsequently enhanced the formation of Mcl-1-Noxa complexes, resulting in the functional neutralization of Mcl-1, an inducer of resistance to ABT-737. On the other hand, SAHA reduced the expression of survivin, an anti-apoptotic molecule that confers drug resistance on ATL cells.
  
  
  CONCLUSIONS
  The combination of ABT-737 with bortezomib or SAHA is promising for the treatment of ATL.
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University, Jonan, Fukuoka, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Kunami
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University, Jonan, Fukuoka, Japan.
authors.forename: Hiroo
authors.initials: H
authors.lastname: Katsuya
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University, Jonan, Fukuoka, Japan.
authors.forename: Rumiko
authors.initials: R
authors.lastname: Nogami
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University, Jonan, Fukuoka, Japan kenjiishitsuka@fukuoka-u.ac.jp.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ishitsuka
authors.affiliation: Department of Internal Medicine, Division of Medical Oncology, Hematology and Infectious Diseases, Fukuoka University, Jonan, Fukuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D009596:Nitrophenols / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: C501332:ABT-737; D051017:Apoptosis Regulatory Proteins; D001713:Biphenyl Compounds; D001897:Boronic Acids; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009596:Nitrophenols; C498702:PMAIP1 protein, human; D010879:Piperazines; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D013449:Sulfonamides; D000077337:Vorinostat; D000069286:Bortezomib
keywords: ABT-737; Adult T-cell leukemia/lymphoma; Bcl-2 family protein; bortezomib; suberoylanilide hydroxamic acid