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-κB), 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-κB 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.
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Authors | Sang Wu Lee, Soo-Keun Yeon, Go Woon Kim, Dong Hoon Lee, Yu Hyun Jeon, Jung Yoo, So Yeon Kim, So Hee Kwon |
Journal | International journal of molecular sciences
(Int J Mol Sci)
Vol. 22
Issue 3
(Jan 29 2021)
ISSN: 1422-0067 [Electronic] Switzerland |
PMID | 33572814
(Publication Type: Journal Article)
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Chemical References |
- A452 compound
- Antineoplastic Agents
- Benzene Derivatives
- Histone Deacetylase Inhibitors
- Bortezomib
- HDAC6 protein, human
- Histone Deacetylase 6
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Topics |
- Antineoplastic Agents
(pharmacology)
- Benzene Derivatives
(pharmacology)
- Bortezomib
(pharmacology)
- Cell Line, Tumor
- Drug Resistance, Neoplasm
(drug effects)
- Histone Deacetylase 6
(antagonists & inhibitors, metabolism)
- Histone Deacetylase Inhibitors
(pharmacology)
- Humans
- Multiple Myeloma
(drug therapy, metabolism)
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