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-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.

SHP2 Inhibitors Show Anti-Myeloma Activity and Synergize With Bortezomib in the Treatment of Multiple Myeloma

“…In addition, looking for novel therapeutic agents is an alternative to overcome bortezomib resistance. It is worth mentioning that previous reports and our research confirmed that BTZ-resistant MM cells have an enhanced activation of the MAPK/ERK pathway ( Lee et al, 2021 ). Thus, we subsequently analyzed whether SHP2 inhibitors could be effective against BTZ-resistant MM cells.…”

State of the Art in Idiopathic Pulmonary Fibrosis

“…The discussions about the side effects and improvement of therapeutic strategies have led to the development of HDAC isoform-selective inhibitors to overcome undesired effects [316]. Until now, most of the agents developed have selectivity for HDAC3, HDAC6 and HDAC8 and have been or are still currently evaluated in preclinical studies for cancer and lung fibrosis [171,189,[234][235][236][237][238]258]. However, numerous HDACs have the very same targets.…”

“…In addition, HDAC6 plays a vital role in the proteolysis pathway of misfolded proteins as it deacetylates α-tubulin for induction of aggresome formation, in which (cytotoxic) ubiquitylated protein aggregates are sequestered for lysosomal degradation and autophagic clearance, thereby attenuating ER stress [187]. HDAC6-dependent autophagy is considered to confer malignancy and aggressiveness to cancer cells and is linked to resistance to proteasome inhibitors (e.g., bortezomib) in patients with various cancers [189]. In addition, HDAC6 is implicated in metastasis formation through the induction of TGF-β-dependent epithelial-mesenchymal transition (EMT) [190,191].…”

“…Due to the broad activity of classical Class I and pan-HDAC inhibitors across HDAC isoforms, the development of second-generation HDAC inhibitors has been focused on improving the selectivity of HDAC inhibitors, resulting in the discovery of a series of isoformspecific HDAC inhibitors. Until now, most of the agents developed and reported in existing articles have selectivity for HDAC3 [234], HDAC6 [174,189,235,236] and HDAC8 [171,237] and are currently being evaluated in preclinical studies. At present, only the HDAC6 inhibitor ACY-1215 (Ricolinostat) has been tested in a phase 2 clinical trial as a treatment strategy for relapsed/refractory lymphoid malignancies (NCT02091063) [238].…”

Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance

“…In combination with 5-Fu, WT161 synergistically inhibited osteosarcoma cells both in vitro and in vivo by increasing the level of PTEN [ 53 ]. HDAC6-selective inhibitor A452 can enhance sensitivity of acquired bortezomib (BTZ)-resistant multiple myeloma cells to bortezomib by inhibiting the activation of ERK and NF-κB in [ 64 ]. The combination of imatinib, a tyrosine kinase inhibitor, and the HDAC6 inhibitor 7b was shown to synergistically induce caspase-dependent apoptotic cell death and decrease the proportion of leukemia stem cells [ 65 ].…”