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

Raninga, Prahlad; Trapani, Giovanna Di; Vučković, Slavica; Bhatia, Maneet; Tonissen, Kathryn Fay

doi:10.18632/oncotarget.3795

Cited by 80 publications

(98 citation statements)

References 61 publications

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“…Our findings complement other studies that showed that modulation of antioxidant systems, glutathione and CuZnSOD, abrogates bortezomib resistance and resensitizes resistant myeloma cells to bortezomib. 15,35 Interestingly, despite higher Trx1 protein levels in bortezomib-resistant myeloma cells, 14 its inhibition using either a specific inhibitor PX-12 or Trx1 anti-sense plasmid did not sensitize bortezomibresistant U266 cells to bortezomib (data not shown). However, the underlying mechanism for this effect remains to be elucidated.…”

Section: Discussionmentioning

confidence: 93%

“…14 Caspase-3 and 9 activity assays Caspase-3 activity was determined in treated and untreated myeloma cells by using Ac-DEVD-AMC (Enzo Life Sciences, http://www.enzolifesciences.com/ALX-260-031), a caspase-3 substrate, as described previously.…”

Section: Cell Viability Measurementmentioning

confidence: 99%

“…Both Trx1 and TrxR1 have been shown to be upregulated in many human cancer types including MM, and correlated with cancer cell proliferation, survival, and chemoresistance. 14,[21][22][23] We have previously shown that bortezomib-resistant cells contained higher Trx1 protein levels compared to parent myeloma cells and its inhibition induced apoptosis in bortezomib-resistant myeloma cells.…”

Section: Introductionmentioning

confidence: 99%

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TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

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Multiple myeloma (MM) is a B-cell malignancy characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Introduction of the proteasome-inhibitor bortezomib has improved MM prognosis and survival; however hypoxia-induced or acquired bortezomib resistance remains a clinical problem. This study highlighted the role of thioredoxin reductase 1 (TrxR1) in the hypoxia-induced and acquired bortezomib resistance in MM. Higher TrxR1 gene expression correlated with high-risk disease, adverse overall survival, and poor prognosis in myeloma patients. We demonstrated that hypoxia induced bortezomib resistance in myeloma cells and increased TrxR1 protein levels. Inhibition of TrxR1 using auranofin overcame hypoxia-induced bortezomib resistance and restored the sensitivity of hypoxicmyeloma cells to bortezomib. Hypoxia increased NF-kb subunit p65 nuclear protein levels and TrxR1 inhibition decreased hypoxia-induced NF-kb p65 protein levels in the nucleus and reduced the expression of NF-kb-regulated genes. In addition, higher TrxR1 protein levels were observed in bortezomib-resistant myeloma cells compared to the na€ ıve cells, and its inhibition using either auranofin or TrxR1-specific siRNAs reversed bortezomib resistance. TrxR1 inhibition reduced p65 mRNA and protein expression in bortezomib-resistant myeloma cells, and also decreased the expression of NF-kb-regulated anti-apoptotic and proliferative genes. Thus, TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance by inhibiting the NF-kb signaling pathway. Our findings demonstrate that elevated TrxR1 levels correlate with the acquisition of bortezomib resistance in MM. We propose considering TrxR1-inhibiting drugs, such as auranofin, either for single agent or combination therapy to circumvent bortezomibresistance and improve survival outcomes of MM patients.

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Section: Discussionmentioning

confidence: 93%

Section: Cell Viability Measurementmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

et al. 2016

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“…Caspase-3 activity assay 0.5 Â 10 6 cells were treated with the appropriate drugs for indicated period of time in 24-wells plate. Caspase-3 activity within the treated and untreated myeloma cell lines and PBMCs was determined as described previously following the cleavage of Ac-DEVD-AMC (Enzo Life Sciences, NY, USA), a caspase-3 substrate [26]. Briefly, treated or untreated cells (0.5 Â 10 6 cells) were pelleted, washed with PBS, re-suspended in 10-15 ml of PBS, and transferred to black-walled 96-wells plate.…”

Section: Western Blot Analysismentioning

confidence: 99%

“…A dicholorofluorescein (DCF) assay was used to determine cellular ROS generation in myeloma cells and control PBMCs as described previously [26]. Briefly, 1 Â 10 6 of treated or untreated cells were washed with PBS and incubated with 10 mM H 2 DCFDA (Molecular probes, CA, USA), a redox sensitive cell permeable dye, for 15 min.…”

Section: Measurement Of Intracellular Ros Generationmentioning

confidence: 99%

Cross-Talk between Two Antioxidants, Thioredoxin Reductase 1 and Heme Oxygenase-1 and Therapeutic Implications in Multiple Myeloma

Raninga

Trapani

Vučković

et al. 2015

Free Radical Biology and Medicine

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a b s t r a c tMultiple myeloma (MM) is characterized by an accumulation of abnormal clonal plasma cells in the bone marrow. Despite recent advancements in anti-myeloma therapies, MM remains an incurable disease. Antioxidant molecules are upregulated in many cancers, correlating with tumor proliferation, survival, and chemoresistance and therefore, have been suggested as potential therapeutic targets. This study investigated the cross-talk between two antioxidant molecules, thioredoxin reductase (TrxR) and heme oxygenase-1 (HO-1), and their therapeutic implications in MM. We found that although auranofin, a TrxR inhibitor, significantly inhibited TrxR activity by more than 50% at lower concentrations, myeloma cell proliferation was only inhibited at higher concentrations of auranofin. Inhibition of TrxR using lower auranofin concentrations induced HO-1 protein expression in myeloma cells. Using a sub-lethal concentration of auranofin to inhibit TrxR activity in conjunction with HO-1 inhibition significantly decreased myeloma cell growth and induced apoptosis. TrxR was shown to regulate HO-1 via the Nrf2 signaling pathway in a ROS-dependent manner. Increased HO-1 mRNA levels were observed in bortezomib-resistant myeloma cells compared to parent cells and HO-1 inhibition restored the sensitivity to bortezomib in bortezomib-resistant myeloma cells. These findings indicate that concurrent inhibition of HO-1 with either a TrxR inhibitor or with bortezomib would improve therapeutic outcomes in MM patients. Hence, our findings further support the need to target multiple antioxidant systems alone or in combination with other therapeutics to improve therapeutic outcomes in MM patients.

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PX‐12 synergistically enhances the therapeutic efficacy of vorinostat under hypoxic tumor microenvironment in oral squamous cell carcinoma in vitro

Akhlaq

Khan

Ahmed

et al. 2023

Drug Development Research

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Hypoxia is a characteristic feature of solid tumors, including oral squamous cell carcinoma (OSCC), which causes therapeutic resistance. The hypoxia‐inducible factor 1‐alpha (HIF‐1α) is a key regulator of hypoxic tumor microenvironment (TME) and a promising therapeutic target against solid tumors. Among other HIF‐1α inhibitors, vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase inhibitor (HDACi) targeting the stability of HIF‐1α, and PX‐12 (1‐methylpropyl 2‐imidazolyl disulfide) is a thioredoxin‐1 (Trx‐1) inhibitor preventing accumulation of HIF‐1α. HDACis are effective against cancers; however, they are accompanied by several side effects along with an emerging resistance against it. This can be overcome by using HDACi in a combination regimen with Trx‐1 inhibitor, as their inhibitory mechanisms are interconnected. HDACis inhibit Trx‐1, leading to an increase in the production of reactive oxygen species (ROS) and inducing apoptosis in cancer cells; thus, the efficacy of HDACi can be elevated by using a Trx‐1 inhibitor. In this study, we have tested the EC50 (half maximal effective concentration) doses of vorinostat and PX‐12 on CAL‐27 (an OSCC cell line) under both normoxic and hypoxic conditions. The combined EC50 dose of vorinostat and PX‐12 is significantly reduced under hypoxia, and the interaction of PX‐12 with vorinostat was evaluated by combination index (CI). An additive interaction between vorinostat and PX‐12 was observed in normoxia, while a synergistic interaction was observed under hypoxia. This study provides the first evidence for vorinostat and PX‐12 synergism under hypoxic TME, at the same time highlighting the therapeutically effective combination of vorinostat and PX‐12 against OSCC in vitro.

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

Cited by 80 publications

References 61 publications

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

TrxR1 inhibition overcomes both hypoxia-induced and acquired bortezomib resistance in multiple myeloma through NF-кβ inhibition

Cross-Talk between Two Antioxidants, Thioredoxin Reductase 1 and Heme Oxygenase-1 and Therapeutic Implications in Multiple Myeloma

PX‐12 synergistically enhances the therapeutic efficacy of vorinostat under hypoxic tumor microenvironment in oral squamous cell carcinoma in vitro

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