-
International Journal of Molecular... Feb 2023Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3' untranslated region of the...
Myotonic dystrophy type 1 (DM1), the most common form of adult muscular dystrophy, is caused by an abnormal expansion of CTG repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. The expanded repeats of the DMPK mRNA form hairpin structures in vitro, which cause misregulation and/or sequestration of proteins including the splicing regulator muscleblind-like 1 (MBNL1). In turn, misregulation and sequestration of such proteins result in the aberrant alternative splicing of diverse mRNAs and underlie, at least in part, DM1 pathogenesis. It has been previously shown that disaggregating RNA foci repletes free MBNL1, rescues DM1 spliceopathy, and alleviates associated symptoms such as myotonia. Using an FDA-approved drug library, we have screened for a reduction of CUG foci in patient muscle cells and identified the HDAC inhibitor, vorinostat, as an inhibitor of foci formation; SERCA1 (sarcoplasmic/endoplasmic reticulum Ca-ATPase) spliceopathy was also improved by vorinostat treatment. Vorinostat treatment in a mouse model of DM1 (human skeletal actin-long repeat; HSA) improved several spliceopathies, reduced muscle central nucleation, and restored chloride channel levels at the sarcolemma. Our in vitro and in vivo evidence showing amelioration of several DM1 disease markers marks vorinostat as a promising novel DM1 therapy.
Topics: Adult; Animals; Humans; Mice; Alternative Splicing; Muscle Cells; Muscle, Skeletal; Myotonic Dystrophy; RNA Splicing; RNA, Messenger; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Trinucleotide Repeat Expansion; Vorinostat
PubMed: 36835205
DOI: 10.3390/ijms24043794 -
The International Journal of... Feb 2022Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene. It is a form of heritable intellectual disability and autism. Despite recent advance in elucidating...
BACKGROUND
Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene. It is a form of heritable intellectual disability and autism. Despite recent advance in elucidating disease mechanisms, there is no efficacious medication. Because de novo drug development is a lengthy process, repurposing the existing FDA-approved drugs offers an opportunity to advance clinical intervention for FXS. Our previous study with transcriptome analysis predicts potential therapeutic effects of vorinostat on FXS.
METHODS
We analyzed the vorinostat-induced transcriptome changes and confirmed its similarity to that induced by trifluoperazine, which was previously shown to correct pathological outcomes associated with FXS. To validate the therapeutic efficacy, we examined vorinostat's effect on correcting the key behavioral and cellular symptoms in a mouse model of FXS.
RESULTS
We found that vorinostat restores object location memory and passive avoidance memory in the Fmr1 knockout mice. For the non-cognitive behavioral symptoms, vorinostat corrected the autism-associated alterations, including repetitive behavior and social interaction deficits. In the open field test, vorinostat dampened hyperactivity in the center area of the arena. Surprisingly, vorinostat did not correct the abnormally elevated protein synthesis in cultured Fmr1 knockout hippocampal neurons, suggesting that different aspects of pathological outcomes may respond differently to a specific therapeutic intervention.
CONCLUSIONS
We used the drug-induced transcriptome signature to predict new application of existing drugs. Our data reveal the therapeutic effects of the FDA-approved drug vorinostat in a mouse model of FXS.
Topics: Animals; Cognition; Disease Models, Animal; Drug Repositioning; Fragile X Mental Retardation Protein; Fragile X Syndrome; Gene Expression Profiling; Hippocampus; Male; Mice; Mice, Knockout; Neurons; Transcriptome; Vorinostat
PubMed: 34791268
DOI: 10.1093/ijnp/pyab081 -
Journal of Inorganic Biochemistry May 2020Vorinostat (suberoylanilide hydroxamic acid; SAHA) and Belinostat are two hydroxamate-based histone deacetylase inhibitors that are used clinically as potent anti-cancer...
Vorinostat (suberoylanilide hydroxamic acid; SAHA) and Belinostat are two hydroxamate-based histone deacetylase inhibitors that are used clinically as potent anti-cancer agents. Their metabolic breakdown into inactive metabolites such as carboxylic acid and glucuronic derivatives results in them having short half-lives, which can negatively impact their pharmacokinetic profiles. Herein we report the potential of both Vorinostat and Belinostat to also act as nitric oxide donors under both chemical and biological ex vivo experimental conditions. More specifically, using ruthenium(III) as an effective NO scavenger, we were able to establish, in the first instance, that both Vorinostat and Belinostat had the capacity to release NO under chemical conditions. Both Vorinostat and Belinostat were then shown to cause vascular relaxation of rat aorta via NO-mediated activation of the haem-containing guanylate cyclase enzyme. A summary of our findings is reported herein.
Topics: Animals; Antineoplastic Agents; Aorta; Guanylate Cyclase; Hydroxamic Acids; Nitric Oxide Donors; Rats; Ruthenium; Sulfonamides; Vasodilation; Vasodilator Agents; Vorinostat
PubMed: 32088592
DOI: 10.1016/j.jinorgbio.2019.110981 -
Blood Oct 2023This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell...
This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. We report the results in cases of cHL. Adult patients with RR cHL who had received ≥1 prior lines of therapy and were ineligible for transplantation were treated in a dose-escalation cohort with 2 dose levels (DLs) and then on an expansion cohort at the recommended phase 2 dose (RP2D) in 21-day cycles. Vorinostat 100 mg twice a day (DL1) and 200 mg twice a day (DL2) was administered orally from days 1 to 5 and 8 to 12; all patients received pembrolizumab 200 mg IV every 3 weeks. The primary end point was safety and determination of RP2D. In total, 32 patients with cHL were enrolled, including 30 at DL2 (RP2D); 78% had received prior anti-programmed cell death 1 (anti-PD-1) therapy, and 56% were PD-1 refractory. Grade ≥3 adverse events (AEs) included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included grade 1 or 2 thyroiditis (13%), grade 1 rash (6%), and grade 3 esophagitis/duodenitis (3%). The overall response rate (ORR) was 72% and complete response (CR) rate was 34%. Patients refractory to prior PD-1 blockade (n = 18) had ORR and CR rates of 56% and 11%, respectively. Pembrolizumab and vorinostat was well tolerated with a high ORR rate in RR cHL including in anti-PD-1-refractory disease. This trial was registered at www.clinicaltrials.gov as #NCT03150329.
Topics: Adult; Humans; Hodgkin Disease; Vorinostat; Programmed Cell Death 1 Receptor; Neoplasm Recurrence, Local; Antibodies, Monoclonal, Humanized
PubMed: 37339586
DOI: 10.1182/blood.2023020485 -
Anti-cancer Drugs Jan 2021T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid...
T-cell lymphoid malignancies (TCLMs) are in need of novel and more effective therapies. The histone deacetylase (HDAC) inhibitors and the synthetic cytotoxic retinoid fenretinide have achieved durable clinical responses in T-cell lymphomas as single agents, and patients who failed prior HDAC inhibitor treatment have responded to fenretinide. We have previously shown fenretinide synergized with the class I HDAC inhibitor romidepsin in preclinical models of TCLMs. There exist some key differences between HDAC inhibitors. Therefore, we determined if the pan-HDAC inhibitor vorinostat synergizes with fenretinide. We demonstrated cytotoxic synergy between vorinostat and fenretinide in nine TCLM cell lines at clinically achievable concentrations that lacked cytotoxicity for non-malignant cells (fibroblasts and blood mononuclear cells). In vivo, vorinostat + fenretinide + ketoconazole (enhances fenretinide exposures by inhibiting fenretinide metabolism) showed greater activity in subcutaneous TCLM xenograft models than other groups. Fenretinide + vorinostat increased reactive oxygen species (ROS, measured by 2',7'-dichlorodihydrofluorescein diacetate dye), resulting in increased apoptosis (via transferase dUTP nick end labeling assay) and histone acetylation (by immunoblotting). The synergistic cytotoxicity, apoptosis, and histone acetylation of fenretinide + vorinostat was abrogated by the antioxidant vitamin C. Like romidepsin, vorinostat combined with fenretinide achieved synergistic cytotoxic activity and increased histone acetylation in preclinical models of TCLMs, but not in non-malignant cells. As vorinostat is an oral agent and not a P-glycoprotein substrate it may have advantages in such combination therapy. These data support conducting a clinical trial of vorinostat combined with fenretinide in relapsed and refractory TCLMs.
Topics: Adolescent; Adult; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Proliferation; Child; Child, Preschool; Drug Synergism; Fenretinide; Humans; Infant, Newborn; Lymphoma, T-Cell; Mice; Mice, Nude; Middle Aged; Prognosis; Reactive Oxygen Species; Tumor Cells, Cultured; Vorinostat; Xenograft Model Antitumor Assays; Young Adult
PubMed: 33079733
DOI: 10.1097/CAD.0000000000001008 -
Bioorganic Chemistry Sep 2021Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of...
Hydroxamic acid derivatives constitute an interesting novel class of antitumor agents. Three of them, including vorinostat, are approved drugs for the treatment of malignancies, while several others are currently under clinical trials. In this work, we present new vorinostat analogs containing the benzoxazole ring as the cap group and various linkers. The benzoxazole-based analogs were synthesized starting either from 2-aminobenzoxazole, through conventional coupling, or from benzoxazole, through a metal-free oxidative amination. All the synthesized compounds were evaluated for their antiproliferative activity on three diverse human cancer cell lines (A549, Caco-2 and SF268), in comparison to vorinostat. Compound 12 (GK601), carrying a benzoxazole ring replacement for the phenyl ring of vorinostat, was the most potent inhibitor of the growth of three cell lines (IC 1.2-2.1 μΜ), similar in potency to vorinostat. Compound 12 also inhibited human HDAC1, HDAC2 and HDAC6 like vorinostat. This new analog also showed antiproliferative activity against two colon cancer cell lines genetically resembling pseudomyxoma peritonei (PMP), namely HCT116 GNAS R201C/+ and LS174T (IC 0.6 and 1.4 μΜ, respectively) with potency comparable to vorinostat (IC 1.1 and 2.1 μΜ, respectively).
Topics: Antineoplastic Agents; Benzoxazoles; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; Molecular Structure; Structure-Activity Relationship; Tumor Cells, Cultured; Vorinostat
PubMed: 34229198
DOI: 10.1016/j.bioorg.2021.105132 -
Experimental Hematology Apr 2019BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological...
BCR-ABL-negative myeloproliferative neoplasms (MPNs) are driven by JAK-STAT pathway activation, but epigenetic alterations also play an important pathophysiological role. These can be pharmacologically manipulated with histone deacetylase inhibitors (HDACIs), which have proven to be clinically effective in the treatment of MPNs but exhibit dose-limiting toxicity. The treatment of primary MPN cells with vorinostat modulates the expression of genes associated with apoptosis, cell cycle, inflammation, and signaling. The induction of this transcriptional program results in decreased cellular viability, paralleled by a decrease in levels of reactive oxygen species (ROS). In vitro manipulation of ROS levels revealed that the reduction of ROS levels promoted apoptosis. When vorinostat was combined with antioxidant agents, the apoptosis of MPN cells increased in a synergistic manner. The results described here suggest a novel and promising therapeutic strategy combining HDACIs with ROS-reducing agents to treat MPNs.
Topics: Adult; Aged; Antioxidants; Apoptosis; Cell Line, Tumor; Drug Synergism; Female; Hematologic Neoplasms; Humans; Male; Middle Aged; Myeloproliferative Disorders; Reactive Oxygen Species; Signal Transduction; Vorinostat
PubMed: 30769020
DOI: 10.1016/j.exphem.2019.02.002 -
Vorinostat combined with brigatinib overcomes acquired resistance in EGFR-C797S-mutated lung cancer.Cancer Letters Jun 2021The development of a new generation of tyrosine kinase inhibitors (TKIs) has improved the treatment response in lung adenocarcinomas. However, acquired resistance often...
The development of a new generation of tyrosine kinase inhibitors (TKIs) has improved the treatment response in lung adenocarcinomas. However, acquired resistance often occurs due to new epidermal growth factor receptor (EGFR) mutations. In particular, the C797S mutation confers drug resistance to T790M-targeting EGFR TKIs. To address C797S resistance, a promising therapeutic avenue is combination therapy that targets both total EGFR and acquired mutations to increase drug efficacy. We showed that combining vorinostat, a histone deacetylase inhibitor (HDACi), with brigatinib, a TKI, enhanced antitumor effects in primary culture and cell lines of lung adenocarcinomas harboring EGFR L858R/T790M/C797S mutations (EGFR-3M). While EGFR phosphorylation was decreased by brigatinib, vorinostat reduced total EGFR-3M (L858R/T790M/C797S) proteins through STUB1-mediated ubiquitination and degradation. STUB1 preferably ubiquitinated other EGFR mutants and facilitated protein turnover compared to EGFR-WT. The association between EGFR and STUB1 required the functional chaperone-binding domain of STUB1 and was further enhanced by vorinostat. Finally, STUB1 levels modulated EGFR downstream functions. Low STUB1 expression was associated with significantly poorer overall survival than high STUB1 expression in patients harboring mutant EGFR. Vorinostat combined with brigatinib significantly improved EGFR-TKI sensitivity to EGFR C797S by inducing EGFR-dependent cell death and may be a promising therapy in treating C797S-resistant lung adenocarcinomas.
Topics: Adenocarcinoma of Lung; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; ErbB Receptors; HEK293 Cells; Humans; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mutation; Organophosphorus Compounds; Pyrimidines; Random Allocation; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 33775711
DOI: 10.1016/j.canlet.2021.03.022 -
Medicinal Research Reviews Nov 2017Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade,... (Review)
Review
Histone deacetylases (HDACs) play a crucial role in the remodeling of chromatin, and are involved in the epigenetic regulation of gene expression. In the last decade, inhibition of HDACs came out as a target for specific epigenetic changes associated with cancer and other diseases. Until now, more than 20 HDAC inhibitors (HDACIs) have entered clinical studies, and some of them (e.g., vorinostat, romidepsin) have been approved for the treatment of cutaneous T-cell lymphoma. This review provides an overview of current knowledge, progress, and molecular mechanisms of HDACIs, covering a period from 2011 until 2015.
Topics: Animals; Clinical Trials as Topic; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Neoplasms; Small Molecule Libraries; Vorinostat
PubMed: 28181261
DOI: 10.1002/med.21437 -
European Journal of Pharmacology Oct 2021Vorinostat is a histone deacetylase inhibitor (HDACi) that was demonstrated in our previous study to inhibit the proliferation, migration, and invasion of cervical...
Vorinostat is a histone deacetylase inhibitor (HDACi) that was demonstrated in our previous study to inhibit the proliferation, migration, and invasion of cervical cancer cells by regulating the PI3K/Akt signaling pathway. However, the molecular mechanism of vorinostat in cervical cancer treatment remains to be further elucidated. A nude mouse xenograft model was established to analyze the antitumor effect of vorinostat in vivo. The combination of iTRAQ-based proteomics and parallel reaction monitoring (PRM) technology has proven to be an efficient and reliable method to identify potential targets for cancer chemotherapy. In this study, 254 differentially expressed proteins in vorinostat-treated cervical cancer cells, among which 180 were upregulated and 74 were downregulated, were identified by using an iTRAQ-based proteomic strategy. Subsequent bioinformatic and PRM analysis of these differentially expressed proteins indicated that UBE2C is a promising target of vorinostat in the inhibition of cervical cancer cell proliferation. We confirmed that the expression of endogenous UBE2C in cervical cancer cell lines was significantly higher than that in normal cervical epithelial cell lines. Additionally, we found that vorinostat downregulated the expression of UBE2C, SQSTM1/p62, N-cadherin, vimentin and upregulated E-cadherin in SiHa and HeLa cells. Our results also showed that vorinostat can downregulate the expression of SQSTM1/p62, N-cadherin, and vimentin during the treatment of cervical cancer cells by regulating UBE2C, while upregulating the expression of E-cadherin. In conclusion, vorinostat reverses epithelial-mesenchymal transition by targeting UBE2C and controls the proliferation of cervical cancer cells through the ubiquitination pathway. UBE2C can be used as a promising target for the development of vorinostat treatment strategies.
Topics: Animals; Epithelial-Mesenchymal Transition; Female; HeLa Cells; Humans; Mice; Phosphatidylinositol 3-Kinases; Uterine Cervical Neoplasms; Vorinostat
PubMed: 34331954
DOI: 10.1016/j.ejphar.2021.174399