title: Sulforaphane synergistically enhances the cytotoxicity of arsenic trioxide             in multiple myeloma cells via stress-mediated pathways.
abstract: Persistent paraprotein production in plasma cells necessitates a highly             developed rough endoplasmic reticulum (ER) that is unusually susceptible to perturbations             in protein synthesis. This biology is believed to account for the exquisite sensitivity             of multiple myeloma (MM) to the proteasomal inhibitor bortezomib (BTZ). Despite             remarkable response rates to BTZ in MM, BTZ carries the potential for serious             side-effects and development of resistance. We, therefore, sought to identify             therapeutic combinations that effectively disrupt proteostasis in order to provide             new potential treatments for MM. We found that sulforaphane, a dietary isothiocyanate             found in cruciferous vegetables, inhibits TNFα-induced Iκβ proteasomal degradation             in a manner similar to BTZ. Like BTZ, sulforaphane synergistically enhances the             cytotoxicity of arsenic trioxide (ATO), an agent with clinical activity in MM.             ATO and sulforaphane co-treatment augmented apoptotic induction as demonstrated             by cleavage of caspase-3, -4 and PARP. The enhanced apoptotic response was dependent             upon production of reactive oxygen species (ROS) as demonstrated by glutathione             depletion and partial inhibition of the apoptotic cascade after pretreatment with             the radical scavenger N-acetyl-cysteine (NAC). Combination treatment resulted             in enhanced ER stress signaling and activation of the unfolded protein response             (UPR), indicative of perturbation of proteostasis. Specifically, combination treatment             caused elevated expression of the molecular chaperone HSP90 (heat shock protein             90) along with increased PERK (protein kinase RNA-like endoplasmic reticulum kinase)             and eIF2α phosphorylation and XBP1 (X-box binding protein 1) splicing, key indicators             of UPR activation. Moreover, increased splicing of XBP1 was apparent upon combination             treatment compared to treatment with either agent alone. Sulforaphane in combination             with ATO effectively disrupts protein homeostasis through ROS generation and induction             of ER stress to culminate in inhibition of protein secretion and apoptotic induction             in MM. Our results suggest that sulforaphane deserves further investigation in             combination with ATO in the treatment of MM.
authors.affiliation: The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY 10016 , USA.
authors.forename: Nicole A
authors.initials: NA
authors.lastname: Doudican
authors.forename: Shih Ya
authors.initials: SY
authors.lastname: Wen
authors.forename: Amitabha
authors.initials: A
authors.lastname: Mazumder
authors.forename: Seth J
authors.initials: SJ
authors.lastname: Orlow
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D053471:Caspases, Initiator / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004357:Drug Synergism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D017879:Isothiocyanates; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000187:drug effects; D013454:Sulfoxides; D013861:Thiocyanates / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D000077237:Arsenic Trioxide; D001152:Arsenicals; D053148:Caspase 3; D053471:Caspases, Initiator; D004268:DNA-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D005978:Glutathione; D018841:HSP90 Heat-Shock Proteins; D051550:I-kappa B Kinase; D017879:Isothiocyanates; D010087:Oxides; D011065:Poly(ADP-ribose) Polymerases; D017382:Reactive Oxygen Species; D000071701:Regulatory Factor X Transcription Factors; D013454:Sulfoxides; D013861:Thiocyanates; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D000071717:X-Box Binding Protein 1; D019892:eIF-2 Kinase; C000605543:XBP1 protein, human; C093516:CASP4 protein, human; C016766:sulforaphane