Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1a 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-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a 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-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a 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-1a protein had shorter overall survival. Conclusions: The HIF-1a 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/ refractorymultiplemyeloma. Itmay also have prognostic significance. © 2014 American Association for Cancer Research.

HIF-1a of bone marrow endothelial cells implies relapse and drug resistance in patients with multiple myeloma and may act as a therapeutic target

ANNESE, TIZIANA;
2014

Abstract

Purpose: To investigate the role of hypoxia-inducible factor-1a (HIF-1a) in angiogenesis and drug resistance of bone marrow endothelial cells of patients with multiple myeloma. Experimental Design: HIF-1a 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-1a inhibition by siRNA or panobinostat (an indirect HIF-1a inhibitor) on the expression of HIF-1a 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-1a protein stabilization and activation that were induced by reactive oxygen species (ROS). The HIF-1a protein correlated with the expression of its proangiogenic targets. The HIF-1a 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-1a protein had shorter overall survival. Conclusions: The HIF-1a 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/ refractorymultiplemyeloma. Itmay also have prognostic significance. © 2014 American Association for Cancer Research.
Aged
Aged
80 and over
Antineoplastic Agents
Bone Marrow Cells
Boronic Acids
Bortezomib
Drug Resistance
Neoplasm
Endothelial Cells
Female
Gene Expression
Gene Expression Regulation
Neoplastic
Humans
Hydroxamic Acids
Hypoxia-Inducible Factor 1
alpha Subunit
Indoles
Kaplan-Meier Estimate
Male
Middle Aged
Multiple Myeloma
Neoplasm Recurrence
Local
Neovascularization
Pathologic
Proteome
Pyrazines
Reactive Oxygen Species
Thalidomide
Transcription
Genetic
Oncology
Cancer Research
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.12572/7775
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