title: Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma.
abstract: Multiple myeloma (MM) is a hematological malignancy characterized by the aberrant accumulation of clonal plasma cells in the bone marrow. Despite recent advancement in anti-myeloma treatment, MM remains an incurable disease. This study showed higher intrinsic oxidative stress and higher Trx1 and TrxR1 protein levels in MM cells compared to normal cells. Drug-induced Trx1 (PX-12) and TrxR1 (Auranofin) inhibition disrupted redox homeostasis resulting in ROS-induced apoptosis in MM cells and a reduction in clonogenic activity. Knockdown of either Trx1 or TrxR1 reduced MM cell viability. Trx1 inhibition by PX-12 sensitized MM cells to undergo apoptosis in response to the NF-κβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-κβ subunit p65 in MM cells. Bortezomib-resistant MM cells contained higher Trx1 protein levels compared to the parental cells and PX-12 treatment resulted in apoptosis. Thus, increased Trx1 enhances MM cell growth and survival and exerts resistance to NF-κβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, QLD, Australia.|Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
authors.forename: Prahlad V
authors.initials: PV
authors.lastname: Raninga
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, QLD, Australia.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Di Trapani
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vuckovic
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, QLD, Australia.|Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
authors.forename: Maneet
authors.initials: M
authors.lastname: Bhatia
authors.affiliation: School of Natural Sciences, Griffith University, Nathan, QLD, Australia.|Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia.
authors.forename: Kathryn F
authors.initials: KF
authors.lastname: Tonissen
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D001310:Auranofin / Q000494:pharmacology; D000069286:Bortezomib / Q000494:pharmacology; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D003474:Curcumin / Q000494:pharmacology; D004220:Disulfides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007963:Leukocytes, Mononuclear; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D054481:Thioredoxin Reductase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000096:biosynthesis
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D004220:Disulfides; D007093:Imidazoles; D009570:Nitriles; C498143:RELA protein, human; D017382:Reactive Oxygen Species; D013450:Sulfones; C491203:TXN protein, human; D051996:Transcription Factor RelA; D001310:Auranofin; D013879:Thioredoxins; D000069286:Bortezomib; C412893:1-methylpropyl-2-imidazolyl disulfide; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D053148:Caspase 3; D003474:Curcumin
keywords: NF-kB; apoptosis; chemoresistance; multiple myeloma; thioredoxin