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Journal of Hematology & Oncology Jul 2015Combination therapy is a key strategy for minimizing drug resistance, a common problem in cancer therapy. The microtubule-depolymerizing agent vincristine is widely used...
BACKGROUND
Combination therapy is a key strategy for minimizing drug resistance, a common problem in cancer therapy. The microtubule-depolymerizing agent vincristine is widely used in the treatment of acute leukemia. In order to decrease toxicity and chemoresistance of vincristine, this study will investigate the effects of combination vincristine and vorinostat (suberoylanilide hydroxamic acid (SAHA)), a pan-histone deacetylase inhibitor, on human acute T cell lymphoblastic leukemia cells.
METHODS
Cell viability experiments were determined by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay, and cell cycle distributions as well as mitochondria membrane potential were analyzed by flow cytometry. In vitro tubulin polymerization assay was used to test tubulin assembly, and immunofluorescence analysis was performed to detect microtubule distribution and morphology. In vivo effect of the combination was evaluated by a MOLT-4 xenograft model. Statistical analysis was assessed by Bonferroni's t test.
RESULTS
Cell viability showed that the combination of vincristine and SAHA exhibited greater cytotoxicity with an IC50 value of 0.88 nM, compared to each drug alone, 3.3 and 840 nM. This combination synergically induced G2/M arrest, followed by an increase in cell number at the sub-G1 phase and caspase activation. Moreover, the results of vincristine combined with an HDAC6 inhibitor (tubastatin A), which acetylated α-tubulin, were consistent with the effects of vincristine/SAHA co-treatment, thus suggesting that SAHA may alter microtubule dynamics through HDAC6 inhibition.
CONCLUSION
These findings indicate that the combination of vincristine and SAHA on T cell leukemic cells resulted in a change in microtubule dynamics contributing to M phase arrest followed by induction of the apoptotic pathway. These data suggest that the combination effect of vincristine/SAHA could have an important preclinical basis for future clinical trial testing.
Topics: Antineoplastic Agents, Phytogenic; Cell Line, Tumor; Cell Survival; Drug Synergism; Humans; Hydroxamic Acids; Leukemia; Vincristine; Vorinostat
PubMed: 26156322
DOI: 10.1186/s13045-015-0176-7 -
Molecular Cancer Therapeutics Feb 2009Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on...
Despite the availability of several Food and Drug Administration-approved drugs, advanced inoperable colorectal cancer remains incurable. In this study, we focused on the development of combined molecular targeted therapies against colon cancer by testing the efficacy of the combination of the histone deacetylase inhibitor vorinostat with the proteasome inhibitor bortezomib to determine if this resulted in synergistic antitumor effects against colorectal cancer. The effects of the histone deacetylase inhibitor vorinostat in combination with the proteasome inhibitor bortezomib on the growth of two colorectal cancer cell lines were assessed with regard to proliferation, cell cycle arrest, and apoptosis. Treatment with the combination of vorinostat and bortezomib resulted in a synergistic decrease in proliferation of both colorectal cancer cell lines compared with treatment with single agents alone. This inhibition was associated with a synergistic increase in apoptosis as measured by caspase-3/7 activity and cleaved poly(ADP-ribose) polymerase. In addition, we observed an increase in the proapoptotic protein BIM and in the number of cells arrested in the G(2)-M phase of the cell cycle. Although p21 levels were significantly increased, short hairpin RNA knockdown of p21 did not lead to changes in proliferation in response to the combination of drugs, indicating that although p21 is a target of these drugs, it is not required to mediate their antiproliferative effects. These data indicate that combination treatment with vorinostat and bortezomib result in synergistic antiproliferative and proapoptotic effects against colon cancer cell lines, providing a rational basis for the clinical use of this combination for the treatment of colorectal cancer.
Topics: Antineoplastic Agents; Apoptosis; Boronic Acids; Bortezomib; Cell Cycle; Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Cell Survival; Colonic Neoplasms; Drug Screening Assays, Antitumor; Drug Synergism; Humans; Hydroxamic Acids; Pyrazines; Signal Transduction; Vorinostat
PubMed: 19174560
DOI: 10.1158/1535-7163.MCT-08-0534 -
Chemical Society Reviews Jul 2008Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical... (Review)
Review
Histone deacetylase (HDAC) proteins are transcription regulators linked to cancer. As a result, multiple small molecule HDAC inhibitors are in various phases of clinical trials as anti-cancer drugs. The majority of HDAC inhibitors non-selectively influence the activities of eleven human HDAC isoforms, which are divided into distinct classes. This tutorial review focuses on the recent progress toward the identification of class-selective and isoform-selective HDAC inhibitors. The emerging trends suggest that subtle differences in the active sites of the HDAC isoforms can be exploited to dictate selectivity.
Topics: Antineoplastic Agents; Binding Sites; Cell Proliferation; Drug Design; Enzyme Inhibitors; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Protein Isoforms; Tumor Cells, Cultured; Vorinostat
PubMed: 18568166
DOI: 10.1039/b703830p -
The Oncologist Feb 2018Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains...
LESSONS LEARNED
Combination regimen with bevacizumab (BEV) and vorinostat is well tolerated in patients with recurrent glioblastoma.Treatment of recurrent glioblastoma remains challenging as this study and others attempt to improve progression-free survival and overall survival with BEV-containing regimens.
BACKGROUND
Recurrent glioblastoma (GBM; World Health Organization grade 4) continues to have a very poor prognosis. Bevacizumab (BEV) has been shown to improve progression-free survival (PFS) in recurrent GBM and is approved by the U.S. Food and Drug Administration for the treatment of recurrent GBM. Combination regimens have been explored, and in this phase II nonrandomized trial, we evaluated the efficacy of BEV combined with histone deacetylase inhibitor vorinostat (VOR) in recurrent GBM.
MATERIALS AND METHODS
In this phase II, single-center, nonrandomized study, subjects with recurrent GBM received BEV 10 mg/kg intravenously (IV) every 2 weeks combined with VOR 400 mg p.o. daily for 7 days on, 7 days off, in a 28-day cycle. The primary endpoint was 6-month PFS (PFS6).
RESULTS
Forty patients with recurrent GBM were enrolled and evaluated. PFS6 was 30.0% (95% confidence interval [CI] 16.8%-44.4%). Median overall survival (OS) was 10.4 months (95% CI 7.6-12.8 months). Overall radiographic response rate was 22.5% based on 9 partial responses. The most common grade 2 and above treatment-related adverse events were lymphopenia (55%), leukopenia (45%), neutropenia (35%), and hypertension (33%). Grade 4 adverse events were leukopenia (3%), neutropenia (3%), sinus bradycardia (3%), and venous thromboembolism (3%). Two deaths occurred in this study, with one due to tumor progression and another possibly related as death not otherwise specified.
CONCLUSION
Combination treatment of BEV and VOR was well tolerated. This combination therapy for this study population did not improve PFS6 or median OS when compared with BEV monotherapy.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Brain Neoplasms; Female; Follow-Up Studies; Glioma; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Non-Randomized Controlled Trials as Topic; Prognosis; Survival Rate; Vorinostat; World Health Organization
PubMed: 29133513
DOI: 10.1634/theoncologist.2017-0501 -
Hematology (Amsterdam, Netherlands) Apr 2012Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating...
Most myeloma patients still experience recurrent relapse and eventually become resistant and/or intolerant of effective agents such as corticosteroids, alkylating agents, immune modulators (lenalidomide and thalidomide) or proteasome inhibitors such as bortezomib. Once this happens average survivals are less than one year. Progress has been made for such patients, however, with the demonstration of clinical benefit of novel proteasome inhibitors (carfilzomib) and immune modulators (pomalidomide). Pomalidomide when used with dexamethasone has activity in 30-60% of patients depending on disease stage. Carfilzomib is an irreversible proteasome inhibitor with favorable toxicity profile (minimal neuropathy) and response rates of 17-54% depending on the disease stage treated. Novel targets are also being explored. Histone deacetylase inhibitors such as vorinostat and panobinostat are in phase II testing although results from a randomized trial combining vorinostat with bortezomib were disappointing. Other small molecules or monoclonal antibodies with novel targets such as kinase inhibitors(AKT, CDK5) and cell surface receptors (e.g. elotuzumab) are undergoing active investigation.
Topics: Antibodies, Monoclonal; Antineoplastic Agents; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Immunologic Factors; Molecular Targeted Therapy; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Thalidomide; Vorinostat
PubMed: 22507794
DOI: 10.1179/102453312X13336169156131 -
Pharmacogenetics and Genomics Oct 2010High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor....
High interindividual pharmacokinetic variability was observed in phase 1 studies of vorinostat (suberoylanilide hydroxamic acid), an oral histone deacetylase inhibitor. Thus, we hypothesized that the variability can be explained by genetic variants of the uridine 5'-diphosphate-glucuronosyltransferases (UGTs) involved in vorinostat metabolism. Baculosomes expressing human UGTs and 52 human liver microsomes were screened for vorinostat glucuronidation activity to identify the potential enzymes and functional variants. UGT2B17 had the largest activity. Human liver microsomes with at least one copy of UGT2B17 showed significantly greater enzymatic activity than those with UGT2B17 null genotype (P<0.004). UGT2B17 plays an important role in vorinostat hepatic glucuronidation and the gene deletion polymorphism may influence vorinostat biotransformation and clearance. The clinical impact of this UGT2B17 genetic variant on vorinostat metabolism and drug effect is unknown.
Topics: Gene Expression Regulation, Enzymologic; Genotype; Glucuronides; Glucuronosyltransferase; Glycosylation; Humans; Hydroxamic Acids; Kinetics; Microsomes, Liver; Pharmacogenetics; RNA, Messenger; Regression Analysis; Substrate Specificity; Vorinostat
PubMed: 20729791
DOI: 10.1097/FPC.0b013e32833e1b37 -
NMR in Biomedicine Feb 2019Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment...
Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM models. First, we confirmed HDAC inhibition in U87 GBM cells and evaluated real-time dynamic metabolic changes using a bioreactor system with live vorinostat-treated or control cells. We found a significant 40% decrease in the C MRS-detectable ratio of hyperpolarized [1- C]lactate to hyperpolarized [1- C]pyruvate, [1- C]Lac/Pyr, and a 37% decrease in the pseudo-rate constant, k , for hyperpolarized [1- C]lactate production, in vorinostat-treated cells compared with controls. To understand the underlying mechanism for this finding, we assessed the expression and activity of lactate dehydrogenase (LDH) (which catalyzes the pyruvate to lactate conversion), its associated cofactor nicotinamide adenine dinucleotide, the expression of monocarboxylate transporters (MCTs) MCT1 and MCT4 (which shuttle pyruvate and lactate in and out of the cell) and intracellular lactate levels. We found that the most likely explanation for our finding that hyperpolarized lactate is reduced in treated cells is a 30% reduction in intracellular lactate levels that occurs as a result of increased expression of both MCT1 and MCT4 in vorinostat-treated cells. In vivo C MRSI studies of orthotopic tumors in mice also showed a significant 52% decrease in hyperpolarized [1- C]Lac/Pyr when comparing vorinostat-treated U87 GBM tumors with controls, and, as in the cell studies, this metabolic finding was associated with increased MCT1 and MCT4 expression in HDAC-inhibited tumors. Thus, the C MRSI-detectable decrease in hyperpolarized [1- C]lactate production could serve as a biomarker of response to HDAC inhibitors.
Topics: Acetylation; Animals; Bioreactors; Carbon-13 Magnetic Resonance Spectroscopy; Cell Line, Tumor; Cell Proliferation; Female; Glioblastoma; Histone Deacetylase Inhibitors; Histones; Lactic Acid; Magnetic Resonance Imaging; Metabolome; Mice, Nude; Monocarboxylic Acid Transporters; Muscle Proteins; Pyruvic Acid; Survival Analysis; Symporters; Vorinostat
PubMed: 30561869
DOI: 10.1002/nbm.4044 -
Antioxidants & Redox Signaling Jul 2015The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies.... (Review)
Review
SIGNIFICANCE
The contribution of epigenetic alterations to cancer development and progression is becoming increasingly clear, prompting the development of epigenetic therapies. Histone deacetylase inhibitors (HDIs) represent one of the first classes of such therapy. Two HDIs, Vorinostat and Romidepsin, are broad-spectrum inhibitors that target multiple histone deacetylases (HDACs) and are FDA approved for the treatment of cutaneous T-cell lymphoma. However, the mechanism of action and the basis for the cancer-selective effects of these inhibitors are still unclear.
RECENT ADVANCES
While the anti-tumor effects of HDIs have traditionally been attributed to their ability to modify gene expression after the accumulation of histone acetylation, recent studies have identified the effects of HDACs on DNA replication, DNA repair, and genome stability. In addition, the HDIs available in the clinic target multiple HDACs, making it difficult to assign either their anti-tumor effects or their associated toxicities to the inhibition of a single protein. However, recent studies in mouse models provide insights into the tissue-specific functions of individual HDACs and their involvement in mediating the effects of HDI therapy.
CRITICAL ISSUES
Here, we describe how altered replication contributes to the efficacy of HDAC-targeted therapies as well as discuss what knowledge mouse models have provided to our understanding of the specific functions of class I HDACs, their potential involvement in tumorigenesis, and how their disruption may contribute to toxicities associated with HDI treatment.
FUTURE DIRECTIONS
Impairment of DNA replication by HDIs has important therapeutic implications. Future studies should assess how best to exploit these findings for therapeutic gain.
Topics: Acetylation; Animals; Chromatin; DNA Repair; DNA Replication; Depsipeptides; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; Hydroxamic Acids; Neoplasms; Vorinostat
PubMed: 24730655
DOI: 10.1089/ars.2014.5915 -
Biology of Blood and Marrow... Feb 2019Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline... (Clinical Trial)
Clinical Trial Comparative Study
Myeloablative conditioning allogeneic hematopoietic cell transplantation (HCT) puts patients at greater risk for significant cognitive and quality of life decline compared with recipients of reduced-intensity conditioning or autologous HCT. Vorinostat, a histone deacetylase inhibitor, has been shown to have neuroprotective and neurorestorative effects in preclinical models of neurologic diseases. Thus, within the context of a myeloablative conditioning phase II clinical trial of vorinostat combined with tacrolimus and methotrexate for graft-versus-host disease prophylaxis, we conducted an ancillary study to evaluate feasibility of assessing associations between vorinostat and neurocognitive function and quality of life (ClinicalTrials.gov NCT02409134). Nine patients (mean age, 53 years; range, 36 to 66) underwent computerized neuropsychological testing (Cogstate) and completed surveys of mood (Patient Health Questionnaire-9), anxiety (General Anxiety Disorder-7), and quality of life (Functional Assessment of Cancer Therapy-General). Control cohorts from a separate concurrent longitudinal study (19 autologous and 18 allogeneic HCT patients, who matched the vorinostat patients on relevant medical and demographic variables) completed the same test battery. All allogeneic patients received busulfan-based myeloablative conditioning and were transplanted with HLA-matched unrelated donors. The total neurocognitive performance score of vorinostat patients did not change significantly across the study duration (ie, baseline, day 30, day 100, and day 160). Depression, anxiety, and quality of life also did not differ significantly across time. In univariate analyses (analysis of variance), vorinostat-treated patients showed no difference in neurocognitive function or quality of life compared with autologous and allogeneic control subjects. However, when medical variables were accounted for in a linear mixed effects regression model, the total neurocognitive performance of vorinostat-treated patients was comparable with autologous control subjects. Notably, autologous control subjects performed significantly better than allogeneic control subjects (estimate, .64; standard error, .23; P ≤ .01). Moreover, a smaller percentage of vorinostat-treated patients were classified as mildly, moderately, or severely impaired across neurocognitive domains as well as time points compared with both control cohorts. Thus, vorinostat may have neurorestorative or neuroprotective effects in the HCT setting. Accordingly, we recognize the need for a future, full-scale randomized controlled trial to further examine this hypothesis.
Topics: Adult; Aged; Allografts; Autografts; Cognition; Female; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Male; Middle Aged; Neuroprotective Agents; Quality of Life; Transplantation Conditioning; Unrelated Donors; Vorinostat
PubMed: 30244099
DOI: 10.1016/j.bbmt.2018.09.015 -
Blood Sep 2020
Topics: HIV Infections; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Vorinostat
PubMed: 32957115
DOI: 10.1182/blood.2020006651