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HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

ABSTRACT: Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-?B), in acquired BTZ-resistant MM cells. Combination treatment of A452 and BTZ or carfilzomib (CFZ) synergistically reduces BTZ-resistant markers. Additionally, A452 synergizes with BTZ or CFZ to inhibit the activation of NF-?B and signal transducer and activator of transcription 3 (STAT3), resulting in decreased expressions of low-molecular-mass polypeptide 2 (LMP2) and LMP7. Furthermore, combining A452 with BTZ or CFZ leads to synergistic cancer cell growth inhibition, viability decreases, and apoptosis induction in the BTZ-resistant MM cells. Overall, the synergistic effect of A452 with CFZ is more potent than that of A452 with BTZ in BTZ-resistant U266 cells. Thus, our findings reveal the HDAC6-selective inhibitor as a promising therapy for BTZ-chemoresistant MM.

SUBMITTER: Lee SW

PROVIDER: S-EPMC7866276 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

Lee Sang Wu SW Yeon Soo-Keun SK Kim Go Woon GW Lee Dong Hoon DH Jeon Yu Hyun YH Yoo Jung J Kim So Yeon SY Kwon So Hee SH

International journal of molecular sciences 20210129 3

Although multiple myeloma (MM) patients benefit from standard bortezomib (BTZ) chemotherapy, they develop drug resistance, resulting in relapse. We investigated whether histone deacetylase 6 (HDAC6) inhibitor A452 overcomes bortezomib resistance in MM. We show that HDAC6-selective inhibitor A452 significantly decreases the activation of BTZ-resistant markers, such as extracellular signal-regulated kinases (ERK) and nuclear factor kappa B (NF-κB), in acquired BTZ-resistant MM cells. Combination t ...[more]

PMID: 33572814

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Project description: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.

Dataset Information

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

Publications

HDAC6-Selective Inhibitor Overcomes Bortezomib Resistance in Multiple Myeloma.

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