Chidamide, a subtype-selective histone deacetylase inhibitor, enhances Bortezomib effects in multiple myeloma therapy.
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ABSTRACT:
SUBMITTER: He Y
PROVIDER: S-EPMC8425211 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Histone deacetylases are promising therapeutic targets in hematological malignancies. In the work herein, we investigated the effect of chidamide, a new subtype-selective histone deacetylase inhibitor that was independently produced in China, on multiple myeloma and its associated bone diseases using different models. The cytotoxicity of chidamide toward myeloma is due to its induction of cell apoptosis and cell cycle arrest by increasing the levels of caspase family proteins p21 and p27, among others. Furthermore, chidamide exhibited significant cytotoxicity against myeloma cells co-cultured with bone mesenchymal stromal cells and chidamide-pretreated osteoclasts. Importantly, chidamide suppressed osteoclast differentiation and resorption in vitro by dephosphorylating p-ERK, p-p38, p-AKT and p-JNK and inhibiting the expression of Cathepsin K, NFATc1 and c-fos. Finally, chidamide not only prevented tumor-associated bone loss in a disseminated murine model by partially decreasing the tumor burden but also prevented rapid receptor activator of nuclear factor ?-? ligand (RANKL)-induced bone loss in a non-tumor-bearing mouse model. Based on our results, chidamide exerted dual anti-myeloma and bone-protective effects in vitro and in vivo These findings strongly support the potential clinical use of this drug as a treatment for multiple myeloma in the near future.
| S-EPMC6068041 | biostudies-literature
Project description:Purpose: Histone deacetylase (HDAC) inhibition improves the efficacy of proteasome inhibition for multiple myeloma but adds substantial toxicity. Preclinical models suggest that the observed synergy is due to the role of HDAC6 in mediating resistance to proteasome inhibition via the aggresome/autophagy pathway of protein degradation.Experimental Design: We conducted a phase I/II trial of the HDAC6-selective inhibitor ricolinostat to define the safety, preliminary efficacy, and recommended phase II dose in combination with standard proteasome inhibitor therapy. Patients with relapsed or refractory multiple myeloma received oral ricolinostat on days 1-5 and 8-12 of each 21-day cycle.Results: Single-agent ricolinostat therapy resulted in neither significant toxicity nor clinical responses. Combination therapy with bortezomib and dexamethasone was well-tolerated during dose escalation but led to dose-limiting diarrhea in an expansion cohort at a ricolinostat dose of 160 mg twice daily. Combination therapy at a ricolinostat dose of 160 mg daily in a second expansion cohort was well tolerated, with less severe hematologic, gastrointestinal, and constitutional toxicities compared with published data on nonselective HDAC inhibitors. The overall response rate in combination with daily ricolinostat at ≥160 mg was 37%. The response rate to combination therapy among bortezomib-refractory patients was 14%. Samples taken during therapy showed dose-dependent increases of acetylated tubulin in peripheral blood lymphocytes.Conclusions: At the recommended phase II dose of ricolinostat of 160 mg daily, the combination with bortezomib and dexamethasone is safe, well-tolerated, and active, suggesting that selective inhibition of HDAC6 is a promising approach to multiple myeloma therapy. Clin Cancer Res; 23(13); 3307-15. ©2017 AACR.
| S-EPMC5496796 | biostudies-literature
Project description: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.
| S-EPMC7866276 | biostudies-literature
Project description:ObjectiveThe recurrence or progression under endocrine therapy in hormone receptor-positive (HR+) advanced breast cancer (ABC) remained a critical clinical challenge. Chidamide is an oral subtype-selective histone deacetylase (HDAC) inhibitor with multiple functions in tumor growth inhibition and microenvironment modulation via epigenetic reprogramming. The purpose of this study was to evaluate the safety, pharmacokinetics (PK), and preliminary efficacy of chidamide in combination with exemestane in HR+ ABC patients.MethodsEligible patients were postmenopausal women with HR+ ABC recurrent or progressed to at least one endocrine therapy. Blood samples were obtained in the run-in period and the first day of combination treatment for PK analysis. In combination treatment, patients were given exemestane 25 mg daily and chidamide 30 mg twice a week (BIW) until progression of disease or intolerable toxicities. A treatment cycle was defined as 4 weeks. Safety, PK parameters, and preliminary efficacy were evaluated.ResultsA total of 20 patients were enrolled between July and December, 2015. The median number of treatments cycle was 5.2 (20.8 weeks) with 2 patients still on treatment at the data cut-off date of October, 2017. The treatment-related adverse events (AE) ≥ grade 3 in more than 2 patients were neutropenia (35%), thrombocytopenia (30%), and leucopenia (20%). The plasma exposure of exemestane was consistent in the presence or absence of chidamide. A slight increase in chidamide exposure was noted in the presence of exemestane, probably due to the inter- and intra-patient variations. The best response in 16 evaluable patients was assessed by Response Evaluation Criteria in Solid Tumors (RECIST), including 4 patients with partial response, 10 patients with stable disease. The median progression-free survival (PFS) was 7.6 months.ConclusionsThe combination of chidamide with exemestane was generally well tolerated with promising preliminary efficacy in HR+ ABC patients. The overall results from this study encourage further pivotal trial in this patient population.
| S-EPMC6328505 | biostudies-literature
Project description:Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients. Panobinostat degraded PPP3CA, a degradation that should have been induced by inhibition of the chaperone function of heat shock protein 90 (HSP90). Cotreatment with HDAC inhibitors and FK506 led to an enhanced antimyeloma effect with a greater PPP3CA reduction compared with HDAC inhibitors alone both in vitro and in vivo. In addition, this combination treatment efficiently blocked osteoclast formation, which results in osteolytic lesions. The poor response and short PFS duration observed in the bortezomib-containing therapies of patients with high PPP3CA suggested its relevance to bortezomib resistance. Moreover, bortezomib and HDAC inhibitors synergistically suppressed MM cell viability through PPP3CA inhibition. Our findings underscore the usefulness of calcineurin-targeted therapy in MM patients, including patients who are resistant to bortezomib.
| S-EPMC5033869 | biostudies-literature
Project description:AimMultiple myeloma (MM) is a hematological malignancy of antibody-producing mature B cells or plasma cells. The proteasome inhibitor, bortezomib, was the first-in-class compound to be FDA approved for MM and is frequently utilized in induction therapy. However, bortezomib refractory disease is a major clinical concern, and the efficacy of the pan-histone deacetylase inhibitor (HDACi), panobinostat, in bortezomib refractory disease indicates that HDAC targeting is a viable strategy. Here, we utilized isogenic bortezomib resistant models to profile HDAC expression and define baseline and HDACi-induced expression patterns of individual HDAC family members in sensitive vs. resistant cells to better understanding the potential for targeting these enzymes.MethodsGene expression of HDAC family members in two sets of isogenic bortezomib sensitive or resistant myeloma cell lines was examined. These cell lines were subsequently treated with HDAC inhibitors: panobinostat or vorinostat, and HDAC expression was evaluated. CRISPR/Cas9 knockdown and pharmacological inhibition of specific HDAC family members were conducted.ResultsInterestingly, HDAC6 and HDAC7 were significantly upregulated and downregulated, respectively, in bortezomib-resistant cells. Panobinostat was effective at inducing cell death in these lines and modulated HDAC expression in cell lines and patient samples. Knockdown of HDAC7 inhibited cell growth while pharmacologically inhibiting HDAC6 augmented cell death by panobinostat.ConclusionOur data revealed heterogeneous expression of individual HDACs in bortezomib sensitive vs. resistant isogenic cell lines and patient samples treated with panobinostat. Cumulatively our findings highlight distinct roles for HDAC6 and HDAC7 in regulating cell death in the context of bortezomib resistance.
| S-EPMC8653980 | biostudies-literature
Project description:Novel agents have made the management of chronic lymphocytic leukemia (CLL) more promising and personalized. However, long-term treatment is still warranted which may result in toxicity and resistance. Thus, new combination therapy may help achieve deeper remission and limited-duration therapy. Histone deacetylase inhibitors (HDACi) can affect many tumors by modulating key biological functions including autophagy. Studies have shown that some novel targeted agents including ibrutinib induce autophagy. This study aimed to explore the effect of oral HDAC inhibitor, chidamide, on CLL cells as well as the role of autophagy in this process. Here, we showed that autophagy flux in CLL cells was inhibited by chidamide via post-transcriptional modulation and chidamide had cytostatic and cytotoxic effects on CLL cells. Besides, the pro-survival role of autophagy in CLL cells was validated by using autophagy inhibitor and knocking down critical autophagy gene. Notably, a combination of chidamide and ibrutinib showed significant synergism and downregulated ibrutinib-induced autophagy. This work highlights the therapeutic potential of chidamide via its effect on autophagy, especially in combination with ibrutinib.
| S-EPMC7485718 | biostudies-literature
Project description:Recently tumor necrosis factor receptor super family member 18 (TNFRSF18, also called GITR) has been identified as a novel tumor suppressor gene in Multiple Myeloma (MM), undergoing aberrant DNA methylation-mediated gene expression silencing. Furthermore, the expression of GITR blocks canonical NF-κB activation in MM cells in response to TNFα. Bortezomib, a proteasome inhibitor, can induce NF-κB activation, which may significantly influence the drug response in MM patients. In this study, we aim to elucidate if GITR status is associated with response to Bortezomib in MM cells through regulating GITR mediated NF-κB blockade. We found that GITR was significantly downregulated in MM patients and cell lines. Overexpression of GITR inhibited non-canonical NF-κB activation induced by TNFα. Moreover, NF-κB inhibitor induced apoptosis in GITR-deficient MM cells in response to TNFα. In addition, overexpression of GITR could inhibit Bortezomib-induced NF-κB activation and enhance the cytotoxicity of Bortezomib in GITR-deficient MM cell line (MM1.S). In contrast, knockdown of GITR attenuated the cytotoxic effect of Bortezomib on GITR proficient MM (RPMI) cell line and increased NF-κB activation. Finally, overexpression of GITR enhanced the sensitivity to Bortezomib in co-culture with bone marrow stromal cells and significantly reduced the tumor growth in MM1.S xenograft mice. In conclusion, we demonstrated that GITR expression can enhance the sensitivity to Bortezomib by inhibiting Bortezomib-induced NF-κB activation.
| S-EPMC4431824 | biostudies-literature
Project description:Histone deacetylases (HDAC) are therapeutic targets in multiple cancers. ACY241, an HDAC6 selective inhibitor, has shown anti-multiple myeloma (MM) activity in combination with immunomodulatory drugs and proteasome inhibitors. Here we show ACY241 significantly reduces the frequency of CD138+ MM cells, CD4+CD25+FoxP3+ regulatory T cells, and HLA-DRLow/-CD11b+CD33+ myeloid-derived suppressor cells; and decreases expression of PD1/PD-L1 on CD8+ T cells and of immune checkpoints in bone marrow cells from myeloma patients. ACY241 increased B7 (CD80, CD86) and MHC (Class I, Class II) expression on tumor and dendritic cells. We further evaluated the effect of ACY241 on antigen-specific cytotoxic T lymphocytes (CTL) generated with heteroclitic XBP1unspliced184-192 (YISPWILAV) and XBP1spliced367-375 (YLFPQLISV) peptides. ACY241 induces co-stimulatory (CD28, 41BB, CD40L, OX40) and activation (CD38) molecule expression in a dose- and time-dependent manner, and anti-tumor activities, evidenced by increased perforin/CD107a expression, IFN-γ/IL-2/TNF-α production, and antigen-specific central memory CTL. These effects of ACY241 on antigen-specific memory T cells were associated with activation of downstream AKT/mTOR/p65 pathways and upregulation of transcription regulators including Bcl-6, Eomes, HIF-1 and T-bet. These studies therefore demonstrate mechanisms whereby ACY241 augments immune response, providing the rationale for its use, alone and in combination, to restore host anti-tumor immunity and improve patient outcome.
| S-EPMC6537609 | biostudies-literature
Project description:Epigenetic dysregulation is a hallmark of cancer, including multiple myeloma. Inhibitors of histone deacetylases (HDACs) induce DNA hyperacetylation by inhibiting removal of acetyl groups from amino tails on histone proteins, thereby uncoiling condensed chromatin favoring transcription of silenced genes, including tumor suppressor genes. Romidepsin is an HDAC inhibitor that exhibits antiproliferative and apoptotic effects against multiple myeloma cell lines.A phase 2 trial was performed of romidepsin in patients with multiple myeloma who were refractory to standard therapy. Treatment was comprised of romidepsin (13 mg/m²) given as a 4-hour intravenous infusion on Days 1, 8, and 15 every 28 days). Thirteen patients received a median of 2 cycles of therapy (range, 1-7 cycles).Although no patients had an objective response, 4 of 12 patients with secretory myeloma exhibited evidence of M-protein stabilization, and several other patients experienced improvement in bone pain and resolution of hypercalcemia.The results of the current study demonstrate that romidepsin, as a single agent, is unlikely to be associated with a response rate of ?30% in patients with refractory myeloma, although there was some clinical evidence suggesting a biological effect associated with therapy.
| S-EPMC3010462 | biostudies-literature