ArticleJournal of hematology & oncology2018
Inhibition of thioredoxin activates mitophagy and overcomes adaptive bortezomib resistance in multiple myeloma.
Article in Journal of hematology & oncology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 57 citations in OpenAlex.
- The role of antioxidants in multiple myeloma: diagnostic, prognostic, and therapeutic applications: a narrative review.Therapeutic advances in hematology · 2026Review
- Multidirectional in silico and in vitro Research for the Pharmaceutical Potential of Fibigia Clypeata (L.) Medik: Phytochemical, Antimicrobial, and Antimyeloma Properties.ChemistryOpen · 2025Article
- Optimized Monothiol Thioredoxin Derivative (ORP100S) Protects In Vitro and In Vivo from Radiation and Chemotoxicity Without Promoting Tumor Proliferation.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Unveiling the Role of Selenium in Child Development: Impacts on Growth, Neurodevelopment and Immunity.Journal of clinical medicine · 2025Review
- Boanmycin overcomes bortezomib resistance by inducing DNA damage and endoplasmic reticulum functional impairment in multiple myeloma.Biology direct · 2025Article
- Disulfidptosis: a new target for central nervous system disease therapy.Frontiers in neuroscience · 2025Review
- Acquired Bortezomib Resistance in Multiple Myeloma: From Mechanisms to Strategy.Current treatment options in oncology · 2024Review
- The Role of Thioredoxin System in Shank3 Mouse Model of Autism.Journal of molecular neuroscience : MN · 2024Article
- Different Strategies to Overcome Resistance to Proteasome Inhibitors-A Summary 20 Years after Their Introduction.International journal of molecular sciences · 2024Review
- Tigecycline Opposes Bortezomib Effect on Myeloma Cells Decreasing Mitochondrial Reactive Oxygen Species Production.International journal of molecular sciences · 2024Article
- Thioredoxin (Trx): A redox target and modulator of cellular senescence and aging-related diseases.Redox biology · 2024Review
- Integrative analysis of the prognostic value and immune microenvironment of mitophagy-related signature for multiple myeloma.BMC cancer · 2023Article
- Inhibition of Sphingosine Kinase 2 Results in PARK2-Mediated Mitophagy and Induces Apoptosis in Multiple Myeloma.Current oncology (Toronto, Ont.) · 2023Article
- Thioredoxin-1 regulates self-renewal and differentiation of murine hematopoietic stem cells through p53 tumor suppressor.Experimental hematology & oncology · 2022Article
- PPAR agonists attenuate lenalidomide's anti-myeloma activity in vitro and in vivo.Cancer letters · 2022Article
- TXN inhibitor impedes radioresistance of colorectal cancer cells with decreased ALDH1L2 expression via TXN/NF-κB signaling pathway.British journal of cancer · 2022Article
- Targeting Redox Regulation as a Therapeutic Opportunity against Acute Leukemia: Pro-Oxidant Strategy or Antioxidant Approach?Antioxidants (Basel, Switzerland) · 2022Review
- Mitochondrial transfer/transplantation: an emerging therapeutic approach for multiple diseases.Cell & bioscience · 2022Review
- Metabolic Vulnerabilities in Multiple Myeloma.Cancers · 2022Review
- Tissue Transglutaminase but Not Microbial Transglutaminase Is Inhibited by Exogenous Oxidative Substances in Celiac Disease.International journal of molecular sciences · 2022Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundAlthough current chemotherapy using bortezomib (Velcade) against multiple myeloma in adults has achieved significant responses and even remission, a majority of patients will develop acquired resistance to bortezomib. Increased thioredoxin level has been reported to be associated with carcinogenesis; however, the role of thioredoxin in bortezomib drug resistance of myeloma remains unclear.
methodsWe generated several bortezomib-resistant myeloma cell lines by serially passaging with increased concentrations of bortezomib over a period of 1.5 years. Thioredoxin expression was measured by real-time PCR and western blot.
resultsThe role of thioredoxin in the survival of bortezomib-resistant myeloma cells was determined by specific shRNA knockdown in vitro and in vivo. Thioredoxin inhibitor (PX12) was used to determine the effectiveness of thioredoxin inhibition in the treatment of bortezomib-resistant myeloma cells. The effect of thioredoxin inhibition on mitophagy induction was examined. The correlation of thioredoxin expression with patient overall survival was interrogated. Thioredoxin expression was significantly upregulated in bortezomib-resistant myeloma cells and the change correlated with the increase of bortezomib concentration. Thioredoxin gene knockdown using specific shRNA sensitized bortezomib-resistant myeloma cells to bortezomib efficiency in vitro and in vivo. Similarly, pharmacological inhibition with PX12 inhibited the growth of bortezomib-resistant myeloma cells and overcame bortezomib resistance in vitro and in vivo. Furthermore, inhibition of thioredoxin resulted in the activation of mitophagy and blockage of mitophagy prevented the effects of PX12 on bortezomib-resistant myeloma cells, indicating that mitophagy is the important molecular mechanism for the induction of cell death in bortezomib-resistant myeloma cells by PX12. Moreover, inhibition of thioredoxin resulted in downregulation of phosphorylated mTOR and ERK1/2. Finally, thioredoxin was overexpressed in primary myeloma cells isolated from bortezomib-resistant myeloma patients and overexpression of thioredoxin correlated with poor overall survival in patients with multiple myeloma.
conclusionsOur findings demonstrated that increased thioredoxin plays a critical role in bortezomib resistance in multiple myeloma through mitophagy inactivation and increased mTOR and ERK1/2 phosphorylation. Thioredoxin provides a potential target for clinical therapeutics against multiple myeloma, particularly for bortezomib-resistant/refractory myeloma patients.
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