title: Differentiation induction enhances bortezomib efficacy and overcomes drug resistance in multiple myeloma.
abstract: OBJECTIVE
  It is of clinical importance to find methods to overcome bortezomib resistance. In the current study, we clarified the relationship between resistance to bortezomib and the differentiation status of myeloma cells, and explored the feasibility of induction of differentiation in overcoming bortezomib resistance in myeloma.
  
  
  METHODS
  Cell morphology, immunoglobulin light-chain protein secretion levels, and XBP-1 expression were used to evaluate the differentiation status of myeloma cells. Low dose 2-ME2 alone or in combination with ATRA was used to induce differentiation in myeloma cells.
  
  
  RESULTS
  The differentiation status of myeloma cells was related to myeloma sensitivity to bortezomib. After successful induction of differentiation, the myeloma cells were more sensitive to bortezomib with decreased growth and an increased rate of apoptosis. Induction of differentiation increased the proteasome workload in myeloma cells by increasing immunoglobulin secretion, while reducing proteasome capacity by decreasing proteasome activity. The imbalance between increased proteasome workload and decreased proteasome capacity is a possible mechanism by which induction of differentiation overcomes myeloma resistance to bortezomib.
  
  
  CONCLUSIONS
  The current study demonstrated, for the first time, that myeloma differentiation status is associated with myeloma sensitivity to bortezomib and that induction of differentiation can overcome myeloma resistance to bortezomib.
authors.affiliation: Department of Hematology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
authors.forename: Jing-li
authors.initials: JL
authors.lastname: Gu
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Zheng-hai
authors.initials: ZH
authors.lastname: Zhou
authors.forename: Jun-ru
authors.initials: JR
authors.lastname: Liu
authors.forename: Bei-hui
authors.initials: BH
authors.lastname: Huang
authors.forename: Dong
authors.initials: D
authors.lastname: Zheng
authors.forename: Chang
authors.initials: C
authors.lastname: Su
mesh_terms: D000077584:2-Methoxyestradiol; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002454:Cell Differentiation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology*; D011719:Pyrazines / Q000494:pharmacology*; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D000071717:X-Box Binding Protein 1
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D004268:DNA-Binding Proteins; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D004958:Estradiol; D014212:Tretinoin; D000069286:Bortezomib; D000077584:2-Methoxyestradiol