title: HIF-1α of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target.
abstract: OBJECTIVE
  To investigate the role of hypoxia-inducible factor-1α (HIF-1α) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma.
  
  
  METHODS
  HIF-1α mRNA and protein were evaluated in patients with multiple myeloma endothelial cells (MMEC) at diagnosis, at relapse after bortezomib- or lenalidomide-based therapies or on refractory phase to these drugs, at remission; in endothelial cells of patients with monoclonal gammapathies of undetermined significance (MGUS; MGECs), and of those with benign anemia (controls). The effects of HIF-1α inhibition by siRNA or panobinostat (an indirect HIF-1α inhibitor) on the expression of HIF-1α proangiogenic targets, on MMEC angiogenic activities in vitro and in vivo, and on overcoming MMEC resistance to bortezomib and lenalidomide were studied. The overall survival of the patients was also observed.
  
  
  RESULTS
  Compared with the other endothelial cell types, only MMECs from 45% of relapsed/refractory patients showed a normoxic HIF-1α protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1α protein correlated with the expression of its proangiogenic targets. The HIF-1α inhibition by either siRNA or panobinostat impaired the MMECs angiogenesis-related functions both in vitro and in vivo and restored MMEC sensitivity to bortezomib and lenalidomide. Patients with MMECs expressing the HIF-1α protein had shorter overall survival.
  
  
  CONCLUSIONS
  The HIF-1α protein in MMECs may induce angiogenesis and resistance to bortezomib and lenalidomide and may be a plausible target for the antiangiogenic management of patients with well-defined relapsed/refractory multiple myeloma. It may also have prognostic significance.
authors.affiliation: Authors' Affiliations: Section of Internal Medicine, Department of Biomedical Sciences and Human Oncology; Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy, National Cancer Institute "Giovanni Paolo II", Bari, Italy; Department of Human Anatomy, Histology and Embryology, and Pathological Anatomy, University of Bari Medical School; Hematology Unit, Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Oncologic Hospital; Laboratory of Preclinical and Translational Research, IRCCS Basilicata Cancer Reference Centre, Potenza; Department of Clinical and Experimental Medicine, University of Foggia Medical School, Foggia; Hematology Unit, Ospedale Di Venere, Carbonara di Bari, Bari; and Department of Haematology, Businco Hospital, Cagliari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.forename: Ivana
authors.initials: I
authors.lastname: Catacchio
authors.forename: Simona
authors.initials: S
authors.lastname: Berardi
authors.forename: Annunziata
authors.initials: A
authors.lastname: De Luisi
authors.forename: Antonella
authors.initials: A
authors.lastname: Caivano
authors.forename: Claudia
authors.initials: C
authors.lastname: Piccoli
authors.forename: Vitalba
authors.initials: V
authors.lastname: Ruggieri
authors.forename: Maria Antonia
authors.initials: MA
authors.lastname: Frassanito
authors.forename: Domenico
authors.initials: D
authors.lastname: Ribatti
authors.forename: Beatrice
authors.initials: B
authors.lastname: Nico
authors.forename: Tiziana
authors.initials: T
authors.lastname: Annese
authors.forename: Simona
authors.initials: S
authors.lastname: Ruggieri
authors.forename: Attilio
authors.initials: A
authors.lastname: Guarini
authors.forename: Carla
authors.initials: C
authors.lastname: Minoia
authors.forename: Paolo
authors.initials: P
authors.lastname: Ditonno
authors.forename: Emanuele
authors.initials: E
authors.lastname: Angelucci
authors.forename: Daniele
authors.initials: D
authors.lastname: Derudas
authors.forename: Michele
authors.initials: M
authors.lastname: Moschetta
authors.forename: Franco
authors.initials: F
authors.lastname: Dammacco
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001854:Bone Marrow Cells / Q000378:metabolism*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D007211:Indoles / Q000494:pharmacology; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism* / Q000517:prevention & control; D009389:Neovascularization, Pathologic / Q000378:metabolism; D000077767:Panobinostat; D020543:Proteome / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D014158:Transcription, Genetic
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C497442:HIF1A protein, human; D006877:Hydroxamic Acids; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D020543:Proteome; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013792:Thalidomide; D000069286:Bortezomib; D000077767:Panobinostat; D000077269:Lenalidomide