title: Treatment-induced oxidative stress and cellular antioxidant capacity determine response to bortezomib in mantle cell lymphoma.
abstract: OBJECTIVE
  Proteasome inhibition disrupts protein homeostasis and induces apoptosis. Up to 50% of patients with relapsed mantle cell lymphoma (MCL) respond to bortezomib. We used gene expression profiling to investigate the connection between proteasome inhibition, cellular response, and clinical efficacy.
  
  
  METHODS
  We assessed transcriptional changes in primary tumor cells from five patients during treatment with bortezomib in vivo, and in 10 MCL cell lines exposed to bortezomib in vitro, on Affymetrix microarrays. Key findings were confirmed by western blotting.
  
  
  RESULTS
  MCL cell lines exposed to bortezomib in vitro showed upregulation of endoplasmic reticulum and oxidative stress response pathways. Gene expression changes were strongest in bortezomib-sensitive cells and these cells were also more sensitive to oxidative stress induced by H2O2. Purified tumor cells obtained at several timepoints during bortezomib treatment in 5 previously untreated patients with leukemic MCL showed strong activation of the antioxidant response controlled by NRF2. Unexpectedly, activation of this homeostatic program was significantly stronger in tumors with the best clinical response. Consistent with its proapoptotic function, we found upregulation of NOXA in circulating tumor cells of responding patients. In resistant cells, gene expression changes in response to bortezomib were limited and upregulation of NOXA was absent. Interestingly, at baseline, bortezomib-resistant cells displayed a relatively higher expression of the NRF2 gene-expression signature than sensitive cells (P < 0.001).
  
  
  CONCLUSIONS
  Bortezomib triggers an oxidative stress response in vitro and in vivo. High cellular antioxidant capacity contributes to bortezomib resistance.
authors.affiliation: Hematology Branch, NHLBI, NIH, Building 10, CRC 3-5140, 10 Center Drive, Bethesda, 20892 MD, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Weniger
authors.forename: Edgar G
authors.initials: EG
authors.lastname: Rizzatti
authors.forename: Patricia
authors.initials: P
authors.lastname: Pérez-Galán
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
authors.forename: Qiuyan
authors.initials: Q
authors.lastname: Wang
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Nalini
authors.initials: N
authors.lastname: Raghavachari
authors.forename: Therese
authors.initials: T
authors.lastname: White
authors.forename: Megan M
authors.initials: MM
authors.lastname: Tweito
authors.forename: Kieron
authors.initials: K
authors.lastname: Dunleavy
authors.forename: Yihong
authors.initials: Y
authors.lastname: Ye
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm; D004721:Endoplasmic Reticulum / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism; D051267:NF-E2-Related Factor 2 / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D013312:Stress, Physiological / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001897:Boronic Acids; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex