Inhibition of thioredoxin 1 leads to apoptosis in drug-resistant multiple myeloma

// Prahlad V. Raninga 1,2 , Giovanna Di Trapani 1 , Slavica Vuckovic 3 , Maneet Bhatia 1,2 and Kathryn F. Tonissen 1,2 1 School of Natural Sciences, Griffith University, Nathan, QLD, Australia 2 Eskitis Institute for Drug Discovery, Griffith University, Nathan, QLD, Australia 3 QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia Correspondence to: Kathryn F. Tonissen, email: // Keywords : thioredoxin, multiple myeloma, apoptosis, NF-kB, chemoresistance Received : February 10, 2015 Accepted : March 10, 2015 Published : April 12, 2015 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-кβ inhibitors, BAY 11-7082 and curcumin. PX-12 treatment decreased the expression of the NF-кβ 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-кβ inhibitors. Therefore inhibiting the thioredoxin system may be an effective therapeutic strategy to treat newly diagnosed as well as relapsed/refractory MM.