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International Journal of Medical... 2019T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate... (Review)
Review
T-cell lymphomas are a heterogeneous group of cancers with different pathogenesis and poor prognosis. Histone deacetylases (HDACs) are epigenetic modifiers that modulate many key biological processes. In recent years, HDACs have been fully investigated for their roles and potential as drug targets in T-cell lymphomas. In this review, we have deciphered the modes of action of HDACs, HDAC inhibitors as single agents, and HDACs guided combination therapies in T-cell lymphomas. The overview of HDACs on the stage of T-cell lymphomas, and HDACs guided therapies both as single agents and combination regimens endow great opportunities for the cure of T-cell lymphomas.
Topics: Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cytokines; Depsipeptides; Epigenesis, Genetic; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Lymphoma, T-Cell; Molecular Targeted Therapy; Sulfonamides; Vorinostat
PubMed: 30911277
DOI: 10.7150/ijms.30154 -
British Journal of Haematology Apr 2011Interactions between the histone deacetylase inhibitor belinostat and the proteasome inhibitor bortezomib were investigated in acute myeloid leukaemia (AML) and acute... (Clinical Trial)
Clinical Trial
Bortezomib interacts synergistically with belinostat in human acute myeloid leukaemia and acute lymphoblastic leukaemia cells in association with perturbations in NF-κB and Bim.
Interactions between the histone deacetylase inhibitor belinostat and the proteasome inhibitor bortezomib were investigated in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL) cells. Co-administration of sub-micromolar concentrations of belinostat with low nanomolar concentrations of bortezomib sharply increased apoptosis in both AML and ALL cell lines and primary blasts. Synergistic interactions were associated with interruption of both canonical and non-canonical nuclear factor (NF)-κB signalling pathways, e.g. accumulation of the phosphorylated (S32/S36) form of IκBα, diminished belinostat-mediated RelA/p65 hyperacetylation (K310), and reduced processing of p100 into p52. These events were accompanied by down-regulation of NF-κB-dependent pro-survival proteins (e.g. XIAP, Bcl-xL). Moreover, belinostat/bortezomib co-exposure induced up-regulation of the BH3-only pro-death protein Bim. Significantly, shRNA knock-down of Bim substantially reduced the lethality of belinostat/bortezomib regimens. Administration of belinostat ± bortezomib also induced hyperacetylation (K40) of α-tubulin, indicating histone deacetylase inhibitor 6 inhibition. Finally, in contrast to the pronounced lethality of belinostat/bortezomib toward primary leukaemia blasts, equivalent treatment was relatively non-toxic to normal CD34(+) cells. Together, these findings indicate that belinostat and bortezomib interact synergistically in both cultured and primary AML and ALL cells, and raise the possibilities that up-regulation of Bim and interference with NF-κB pathways contribute to this phenomenon. They also suggest that combined belinostat/bortezomib regimens warrant further attention in acute leukaemias.
Topics: Acetylation; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Bcl-2-Like Protein 11; Boronic Acids; Bortezomib; Drug Synergism; Female; HL-60 Cells; Histone Deacetylase 6; Histone Deacetylases; Humans; Hydroxamic Acids; I-kappa B Kinase; Jurkat Cells; Leukemia, Myeloid, Acute; Male; Membrane Proteins; Phosphorylation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Proto-Oncogene Proteins; Pyrazines; Signal Transduction; Sulfonamides; Transcription Factor RelA; Tubulin; U937 Cells; X-Linked Inhibitor of Apoptosis Protein; bcl-X Protein
PubMed: 21375523
DOI: 10.1111/j.1365-2141.2011.08591.x -
Experimental Hematology & Oncology Feb 2021Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine...
Belinostat in combination with standard cyclophosphamide, doxorubicin, vincristine and prednisone as first-line treatment for patients with newly diagnosed peripheral T-cell lymphoma.
BACKGROUND
Belinostat is a histone deacetylase inhibitor approved for relapsed refractory peripheral T-cell lymphoma (PTCL). The primary objective of this study was to determine the maximum tolerated dose (MTD) of belinostat combined with CHOP (Bel-CHOP). Secondary objectives included safety/tolerability, overall response rate (ORR), and belinostat pharmacokinetics (PK).
METHODS
Patients were ≥ 18 years with histologically confirmed, previously untreated PTCL. Patients received belinostat (1000 mg/m once daily) + standard CHOP for 6 cycles with varying schedules using a 3 + 3 design in Part A. Part B enrolled patients at MTD dose.
RESULTS
Twenty-three patients were treated. One patient experienced DLT (Grade 3 non-hematologic toxicity) on Day 1-3 schedule, resulting in escalation to Day 1-5 schedule (n = 3). No DLTs were observed and Day 1-5 schedule with 1000 mg/m was declared as MTD. Twelve additional patients were enrolled in Part B using MTD. Median relative dose intensity was 98%. All patients experienced adverse events (AEs), including nausea (78%), fatigue (61%), and vomiting (57%). Serious AEs occurred in 43%, with febrile neutropenia (17%) and pyrexia (13%). Overall ORR was 86% with 71% reported CR at MTD. Belinostat PK parameters were similar to single-agent.
CONCLUSIONS
Bel-CHOP was well tolerated and MTD in CHOP combination was the same dose and schedule as single agent dosing.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT01839097.
PubMed: 33602316
DOI: 10.1186/s40164-021-00203-8 -
Biomedical Reports Nov 2015There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing ubiquitinated protein accumulation and...
There is no curative treatment for advanced renal cancer, and a novel treatment approach is urgently required. Inducing ubiquitinated protein accumulation and endoplasmic reticulum (ER) stress has recently emerged as a new approach in the treatment of malignancies. In the present study, we hypothesized that the histone deacetylase inhibitor belinostat would increase the amount of unfolded proteins in cells by inhibiting heat-shock protein (HSP) 90, and that the proteasome inhibitor bortezomib would inhibit their degradation by inhibiting the proteasome, thus causing ubiquitinated protein accumulation and ER stress synergistically. The combination of bortezomib and belinostat induced significant increases in apoptosis and inhibited renal cancer growth synergistically (combination indexes <1). The combination also suppressed colony formation significantly (P<0.05). As co-treatment with the pan-caspase inhibitor Z-VAD-FMK changed the number of Annexin V-positive cells, this combination-induced apoptosis was considered caspase dependent. Mechanistically, the combination synergistically caused ubiquitinated proteins to accumulate and induced ER stress, as evidenced by the increased expression of glucose-regulated protein 78 and HSP70. To the best of our knowledge, this is the first study demonstrating the beneficial combined effect of bortezomib and belinostat in renal cancer cells. The study provides a basis for clinical studies with the combination in patients with advanced renal cancer.
PubMed: 26623018
DOI: 10.3892/br.2015.523 -
RSC Advances Aug 2022Multiple myeloma is a deadly cancer that is a complex and multifactorial disease. In the present study, 12 belinostat derivatives (four resynthesized and eight new),...
Multiple myeloma is a deadly cancer that is a complex and multifactorial disease. In the present study, 12 belinostat derivatives (four resynthesized and eight new), HDAC inhibitors, were resynthesized either Knoevenagel condensation, or Wittig reaction, or Heck reaction. Then an evaluation of the antiproliferative activities against myeloma cells MOPC-315 was carried out. Amongst them, compound 7f was the most bioactive compound with an IC of 0.090 ± 0.016 μM, being 3.5-fold more potent than the reference belinostat (IC = 0.318 ± 0.049 μM). Furthermore, we also confirmed the inhibitory activity of 7f in a cellular model. Additionally, we found that the inhibitory activity of 7f against histone deacetylase 6 catalytic activity (HDAC6) is more potent than that of belinostat. Finally, we observed the strong synergistic interaction between the derivative 7f and the proteasome bortezomib inhibitor (CI = 0.26), while belinostat and bortezomib showed synergism with a CI value of 0.36. Taken together, the above results suggest that 7f is a promising HDAC inhibitor deserving further investigation.
PubMed: 36043105
DOI: 10.1039/d2ra01969h -
Cancer Research Nov 2021Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its...
Cholangiocarcinoma is a form of hepatobiliary cancer with an abysmal prognosis. Despite advances in our understanding of cholangiocarcinoma pathophysiology and its genomic landscape, targeted therapies have not yet made a significant impact on its clinical management. The low response rates of targeted therapies in cholangiocarcinoma suggest that patient heterogeneity contributes to poor clinical outcome. Here we used mass spectrometry-based phosphoproteomics and computational methods to identify patient-specific drug targets in patient tumors and cholangiocarcinoma-derived cell lines. We analyzed 13 primary tumors of patients with cholangiocarcinoma with matched nonmalignant tissue and 7 different cholangiocarcinoma cell lines, leading to the identification and quantification of more than 13,000 phosphorylation sites. The phosphoproteomes of cholangiocarcinoma cell lines and patient tumors were significantly correlated. MEK1, KIT, ERK1/2, and several cyclin-dependent kinases were among the protein kinases most frequently showing increased activity in cholangiocarcinoma relative to nonmalignant tissue. Application of the Drug Ranking Using Machine Learning (DRUML) algorithm selected inhibitors of histone deacetylase (HDAC; belinostat and CAY10603) and PI3K pathway members as high-ranking therapies to use in primary cholangiocarcinoma. The accuracy of the computational drug rankings based on predicted responses was confirmed in cell-line models of cholangiocarcinoma. Together, this study uncovers frequently activated biochemical pathways in cholangiocarcinoma and provides a proof of concept for the application of computational methodology to rank drugs based on efficacy in individual patients. SIGNIFICANCE: Phosphoproteomic and computational analyses identify patient-specific drug targets in cholangiocarcinoma, supporting the potential of a machine learning method to predict personalized therapies.
Topics: Antineoplastic Agents; Bile Duct Neoplasms; Biomarkers, Tumor; Cholangiocarcinoma; Computational Biology; Drug Discovery; Humans; Phosphoproteins; Protein Kinase Inhibitors; Protein Kinases; Proteome; Tumor Cells, Cultured
PubMed: 34551960
DOI: 10.1158/0008-5472.CAN-21-0955 -
British Journal of Clinical Pharmacology Nov 2019The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to...
AIMS
The histone deacetylase inhibitor belinostat has activity in various cancers. Because belinostat is metabolized by the liver, reduced hepatic clearance could lead to excessive drug accumulation and increased toxicity. Safety data in patients with liver dysfunction are needed for this drug to reach its full potential in the clinic.
METHODS
We performed a phase 1 trial to determine the safety, maximum tolerated dose (MTD) and pharmacokinetics of belinostat in patients with advanced cancer and varying degrees of liver dysfunction.
RESULTS
Seventy-two patients were enrolled and divided into cohorts based on liver function. In patients with mild dysfunction, the MTD was the same as the recommended phase 2 dose (1000 mg/m /day). Belinostat was well tolerated in patients with moderate and severe liver dysfunction, although the trial was closed before the MTD in these cohorts could be determined. The mean clearance of belinostat was 661 mL/min/m in patients with normal liver function, compared to 542, 505 and 444 mL/min/m in patients with mild, moderate and severe hepatic dysfunction. Although this trial was not designed to assess clinical activity, of the 47 patients evaluable for response, 13 patients (28%) experienced stable disease.
CONCLUSION
While a statistically significant difference in clearance indicates increased belinostat exposure with worsening liver function, no relationship was observed between belinostat exposure and toxicity. An assessment of belinostat metabolites revealed significant differences in metabolic pathway capability in patients with differing levels of liver dysfunction. Further studies are needed to establish formal dosing guidelines in this patient population.
Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Infusions, Intravenous; Liver; Liver Diseases; Male; Maximum Tolerated Dose; Metabolic Clearance Rate; Middle Aged; Neoplasm Staging; Neoplasms; Severity of Illness Index; Sulfonamides
PubMed: 31271459
DOI: 10.1111/bcp.14054 -
Journal of the Advanced Practitioner in... Mar 2016
Review
PubMed: 28090369
DOI: 10.6004/jadpro.2016.7.2.6 -
Clinical Cancer Research : An Official... Nov 2014This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC)...
PURPOSE
This phase I/II study sought to determine the safety and maximum tolerated dose (MTD) of a novel schedule of belinostat, a histone deacetylase inhibitor (HDAC) administered before and in combination with cisplatin (P), doxorubicin (A), and cyclophosphamide (C) in thymic epithelial tumors (TET). Antitumor activity, pharmacokinetics, and biomarkers of response were also assessed.
EXPERIMENTAL DESIGN
Patients with advanced, unresectable TET received increasing doses of belinostat as a continuous intravenous infusion over 48 hours with chemotherapy in 3-week cycles. In phase II, belinostat at the MTD was used.
RESULTS
Twenty-six patients were enrolled (thymoma, 12; thymic carcinoma, 14). Dose-limiting toxicities at 2,000 mg/m(2) belinostat were grade 3 nausea and diarrhea and grade 4 neutropenia and thrombocytopenia, respectively, in two patients. Twenty-four patients were treated at the MTD of 1,000 mg/m(2) with chemotherapy (P, 50 mg/m(2) on day 2; A, 25 mg/m(2) on days 2 and 3; C, 500 mg/m(2) on day 3). Objective response rates in thymoma and thymic carcinoma were 64% (95% confidence interval, 30.8%-89.1%) and 21% (4.7%-50.8%), respectively. Modulation of pharmacodynamic markers of HDAC inhibition and declines in regulatory T cell (Treg) and exhausted CD8(+) T-cell populations were observed. Decline in Tregs was associated with response (P = 0.0041) and progression-free survival (P = 0.021). Declines in TIM3(+) CD8(+) T cells were larger in responders than nonresponders (P = 0.049).
CONCLUSION
This study identified the MTD of belinostat in combination with PAC and indicates that the combination is active and feasible in TETs. Immunomodulatory effects on Tregs and TIM3(+) CD8(+) T cells warrant further study.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; CD8-Positive T-Lymphocytes; Cisplatin; Cyclophosphamide; Doxorubicin; Female; Humans; Hydroxamic Acids; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms, Glandular and Epithelial; Sulfonamides; Thymus Neoplasms; Translational Research, Biomedical; Young Adult
PubMed: 25189481
DOI: 10.1158/1078-0432.CCR-14-0968 -
British Journal of Cancer Jun 2010This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the...
A phase I study of the safety and pharmacokinetics of the histone deacetylase inhibitor belinostat administered in combination with carboplatin and/or paclitaxel in patients with solid tumours.
BACKGROUND
This phase I study assessed the maximum tolerated dose, dose-limiting toxicity (DLT) and pharmacokinetics of belinostat with carboplatin and paclitaxel and the anti-tumour activity of the combination in solid tumours.
METHODS
Cohorts of three to six patients were treated with escalating doses of belinostat administered intravenously once daily, days 1-5 q21 days; on day 3, carboplatin (area under the curve (AUC) 5) and/or paclitaxel (175 mg m(-2)) were administered 2-3 h after the end of the belinostat infusion.
RESULTS
In all 23 patients received 600-1000 mg m(-2) per day of belinostat with carboplatin and/or paclitaxel. No DLT was observed. The maximal administered dose of belinostat was 1000 mg m(-2) per day for days 1-5, with paclitaxel (175 mg m(-2)) and carboplatin AUC 5 administered on day 3. Grade III/IV adverse events were (n; %): leucopenia (5; 22%), neutropenia (7; 30%), thrombocytopenia (3; 13%) anaemia (1; 4%), peripheral sensory neuropathy (2; 9%), fatigue (1; 4%), vomiting (1; 4%) and myalgia (1; 4%). The pharmacokinetics of belinostat, paclitaxel and carboplatin were unaltered by the concurrent administration. There were two partial responses (one rectal cancer and one pancreatic cancer). A third patient (mixed mullerian tumour of ovarian origin) showed a complete CA-125 response. In addition, six patients showed a stable disease lasting > or =6 months.
CONCLUSION
The combination was well tolerated, with no evidence of pharmacokinetic interaction. Further evaluation of anti-tumour activity is warranted.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Male; Middle Aged; Neoplasms; Paclitaxel; Sulfonamides
PubMed: 20588278
DOI: 10.1038/sj.bjc.6605726