Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2021; 12:948-949.

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

Prahlad V. Raninga, Giovanna Di Trapani, Slavica Vuckovic, Maneet Bhatia and Kathryn F. Tonissen _

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Oncotarget. 2015; 6:15410-15424. https://doi.org/10.18632/oncotarget.3795

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Abstract

Prahlad V. Raninga1,2, Giovanna Di Trapani1, Slavica Vuckovic3, Maneet Bhatia1,2 and Kathryn F. Tonissen1,2

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.


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