College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon 21983, Korea.
Int J Mol Sci. 2021 Jan 29;22(3):1341. doi: 10.3390/ijms22031341.
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.
尽管多发性骨髓瘤（MM）患者受益于标准硼替佐米（BTZ）化疗，但他们会产生耐药性，导致复发。我们研究了组蛋白去乙酰化酶 6（HDAC6）抑制剂 A452 是否可以克服 MM 中的硼替佐米耐药性。我们发现，HDAC6 选择性抑制剂 A452 可显著降低获得性 BTZ 耐药 MM 细胞中 BTZ 耐药标志物（如细胞外信号调节激酶（ERK）和核因子 kappa B（NF-κB））的激活。A452 与 BTZ 或卡非佐米（CFZ）联合治疗可协同降低 BTZ 耐药标志物。此外，A452 与 BTZ 或 CFZ 协同抑制 NF-κB 和信号转导和转录激活因子 3（STAT3）的激活，导致低分子质量多肽 2（LMP2）和 LMP7 的表达减少。此外，A452 与 BTZ 或 CFZ 联合使用可导致 BTZ 耐药 MM 细胞协同抑制癌细胞生长、降低细胞活力和诱导细胞凋亡。总体而言，A452 与 CFZ 的协同作用在 BTZ 耐药 U266 细胞中比 A452 与 BTZ 的协同作用更强。因此，我们的研究结果表明，HDAC6 选择性抑制剂是一种有前途的治疗硼替佐米耐药 MM 的方法。
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