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Epigenomics Jun 2010Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an... (Review)
Review
Reversible histone acetylation on lysine residues, regulated by the opposing activities of histone acetyltransferases and histone deacetylases (HDACs), plays an important role in the regulation of gene expression. Aberrant gene expression resulting from increased HDAC activity and histone hypoacetylation has been observed in human tumors and genetic knockdown studies support a role of HDACs in cancer. Treatment with small-molecule inhibitors of HDAC activity results in anti-tumor effects in a variety of transformed cell lines. Several HDAC inhibitors are in clinical development and show anti-tumor activity in cancer patients. Vorinostat (suberoylanilide hydroxamic acid) was the first HDAC inhibitor approved for the treatment of cancer and will be the focus of this article.
Topics: Acetylation; Animals; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Lysine; Neoplasms; Vorinostat
PubMed: 22121904
DOI: 10.2217/epi.10.20 -
Cell Communication and Signaling : CCS Mar 2024Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling...
Pan-histone deacetylase inhibitor vorinostat suppresses osteoclastic bone resorption through modulation of RANKL-evoked signaling and ameliorates ovariectomy-induced bone loss.
BACKGROUND
Estrogen deficiency-mediated hyperactive osteoclast represents the leading role during the onset of postmenopausal osteoporosis. The activation of a series of signaling cascades triggered by RANKL-RANK interaction is crucial mechanism underlying osteoclastogenesis. Vorinostat (SAHA) is a broad-spectrum pan-histone deacetylase inhibitor (HDACi) and its effect on osteoporosis remains elusive.
METHODS
The effects of SAHA on osteoclast maturation and bone resorptive activity were evaluated using in vitro osteoclastogenesis assay. To investigate the effect of SAHA on the osteoclast gene networks during osteoclast differentiation, we performed high-throughput transcriptome sequencing. Molecular docking and the assessment of RANKL-induced signaling cascades were conducted to confirm the underlying regulatory mechanism of SAHA on the action of RANKL-activated osteoclasts. Finally, we took advantage of a mouse model of estrogen-deficient osteoporosis to explore the clinical potential of SAHA.
RESULTS
We showed here that SAHA suppressed RANKL-induced osteoclast differentiation concentration-dependently and disrupted osteoclastic bone resorption in vitro. Mechanistically, SAHA specifically bound to the predicted binding site of RANKL and blunt the interaction between RANKL and RANK. Then, by interfering with downstream NF-κB and MAPK signaling pathway activation, SAHA negatively regulated the activity of NFATc1, thus resulting in a significant reduction of osteoclast-specific gene transcripts and functional osteoclast-related protein expression. Moreover, we found a significant anti-osteoporotic role of SAHA in ovariectomized mice, which was probably realized through the inhibition of osteoclast formation and hyperactivation.
CONCLUSION
These data reveal a high affinity between SAHA and RANKL, which results in blockade of RANKL-RANK interaction and thereby interferes with RANKL-induced signaling cascades and osteoclastic bone resorption, supporting a novel strategy for SAHA application as a promising therapeutic agent for osteoporosis.
Topics: Female; Animals; Mice; Histone Deacetylase Inhibitors; Vorinostat; Molecular Docking Simulation; Bone Resorption; Signal Transduction; Osteoporosis; Estrogens
PubMed: 38439009
DOI: 10.1186/s12964-024-01525-w -
The Prostate Apr 2023Like DNA methylation, histone modifications are considered important processes for epigenetic alterations in gene function, and abnormally high expression of histone...
Combination with vorinostat enhances the antitumor activity of cisplatin in castration-resistant prostate cancer by inhibiting DNA damage repair pathway and detoxification of GSH.
BACKGROUND
Like DNA methylation, histone modifications are considered important processes for epigenetic alterations in gene function, and abnormally high expression of histone deacetylases (HDACs) plays a key role in many human diseases. In addition to regulating the acetylation levels of histone and non-histone proteins and gene transcription, HDAC inhibitors as antitumor drugs can also affect the DNA damage repair (DDR) pathway in tumor cells. Prostate cancer (PCa) is one of the most heritable malignancies in which DDR pathway defects can be detected in a considerable proportion of cases. Such defects are more prevalent in castration-resistant prostate cancer (CRPC) and are highly enriched in metastatic lesions. There is currently evidence that DDR pathway-deficient PCa is associated with high-risk biological behaviors and response sensitivity to platinum-based chemotherapy. Platinum-based drugs have been used in multiple clinical trials as monotherapy or in combination with other chemotherapeutic agents for the treatment of CRPC.
METHODS
This study evaluated the combined anticancer effect of (cisplatin) CDDP and the HDAC inhibitors vorinostat (SAHA) on three androgen-dependent cell lines PC-3, DU-145, and C4-2B in vitro. The efficacy and safety of SAHA combined with CDDP in the treatment of CRPC were further verified through animal experiments.
RESULTS
The combination of the two drugs increases cytotoxic effects by increasing DNA damage. Our results showed that the SAHA could not only reduce the expression of homologous recombinant repair proteins BRCA2, BRCA1, PARP1, and RAD51, but also decrease enzymes that Reduce the key enzymes of GSH biosynthesis, GSS and GCLC, and GSTP1 which can catalyze the binding of GSH to cisplatin. The intracellular GSH level also decreased with the increase of SAHA concentration, at the same time, the content of intracellular Pt element.
CONCLUSION
The combination of CDDP and SAHA can produce synergistic anticancer effects in androgen-independent PCa cells in vitro and in vivo. Our results open up a new avenue for the effective treatment of CRPC. To optimize the chemotherapy regimen for patients with advanced PCa, it is necessary to further study the molecular mechanism of platinum drugs, HDAC inhibitors, and their combined action.
Topics: Male; Animals; Humans; Vorinostat; Cisplatin; Histone Deacetylase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Androgens; Cell Line, Tumor; Antineoplastic Agents; DNA Damage
PubMed: 36576015
DOI: 10.1002/pros.24479 -
Current Molecular Pharmacology Oct 2021Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects....
BACKGROUND AND AIM
Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects. Vorinostat (VST) has been reported to have antioxidant and anti-inflammatory effects in bothin-vitro and in vivo models. The present study aimed to explore the potential protective effects of VST against CDDP-induced nephrotoxicity in rats.
MATERIALS AND METHODS
The rats were randomly divided into 4 groups; control group, CDDP group (received CDDP 7.5 mg/kg IP single dose 5 days before the end of the experiment), VST group, (received VST 15 mg/kg/day by gastric gavage for 28 days), and CDDP + VST group (received CDDP + VST as above). Blood and kidney samples were collected on the 28th day for biochemical and histopathological examinations.
RESULTS
Administration of CDDP single dose (7.5 mg/kg IP) 5 days before the end of the experiment (at day 23) produced a significant decrease in renal glutathione levels and a significant increase in serum urea nitrogen, creatinine, renal malondialdehyde, tumor necrosis factor-alpha, tumor suppressor protein (p53) and nuclear factor kappa B levels compared to the control group. Pretreatment with VST for 28 days significantly attenuated all unfavorable changes of these parameters. Histopathological analysis showed that VST significantly decreased kidney inflammatory and degenerative changes induced by CDDP. VST also significantly increased Bcl-2 and decreased Caspas- 3 immunoexpression in renal tissues.
CONCLUSION
These results suggest that VST alleviates CDDP-induced nephrotoxicity in rats showing a novel therapeutic potential for the management of nephrotoxicity induced by CDDP.
Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Cisplatin; Creatinine; Kidney; Rats; Vorinostat
PubMed: 33297925
DOI: 10.2174/1874467213666201209104335 -
Biochemical Pharmacology Aug 2020The combination of the multi-kinase and chaperone inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in pancreatic cancer patients has proven to be a... (Clinical Trial)
Clinical Trial
The combination of the multi-kinase and chaperone inhibitor sorafenib and the histone deacetylase inhibitor vorinostat in pancreatic cancer patients has proven to be a safe and efficacious modality (NCT02349867). We determined the evolutionary mechanisms by with pancreatic tumors become resistant to [sorafenib + vorinostat] and developed a new three-drug therapy to circumvent the resistant phenotype. Pancreatic tumors previously exposed to [sorafenib + vorinostat] evolved to activate the receptors ERBB1, ERBB2, ERBB3, c-MET and the intracellular kinase AKT. The irreversible ERBB receptor family and MAP4K inhibitor neratinib significantly enhanced the anti-tumor efficacy of [sorafenib + vorinostat]. We then determined the mechanisms by which neratinib enhanced the efficacy of [sorafenib + vorinostat]. Compared to [sorafenib + vorinostat] or to neratinib alone, the three-drug combination further enhanced the phosphorylation of eIF2α and NFκB and the expression of Beclin1, ATG5 and CD95; and suppressed the levels of β-catenin. Knock down of Beclin1, ATG5, CD95, eIF2 α or NFκB suppressed cell killing whereas knock down of β-catenin enhanced killing. The drugs interacted to increase autophagosome formation; and autophagy and cell killing were suppressed by expression of activated mTOR. A portion of the killing mechanism required CD95 signaling and knock down of NFκB prevented the drugs from increasing CD95 expression. We conclude that neratinib, by down-regulation of evolutionary activated growth factor receptors, may represent a novel follow-on clinical concept after the completion of NCT02349867.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Autophagy; Cell Line, Tumor; Cell Survival; Female; Humans; Male; Mice; Mice, Nude; Pancreatic Neoplasms; Quinolines; Sorafenib; Vorinostat
PubMed: 32504550
DOI: 10.1016/j.bcp.2020.114067 -
Biofouling 2023is a food-borne microorganism that is also a zoonotic bacterial hazard in the food sector. This study determined how well a mixed culture of Kentucky formed biofilms...
is a food-borne microorganism that is also a zoonotic bacterial hazard in the food sector. This study determined how well a mixed culture of Kentucky formed biofilms on plastic (PLA), silicon rubber (SR), rubber gloves (RG), chicken skin and eggshell surfaces. interactions between the histone deacetylase inhibitor-vorinostat (SAHA)-and serotype Kentucky were examined utilizing biofilms. The minimum inhibitory concentration (MIC) of SAHA was 120 µg mL. The addition of sub-MIC (60 µg mL) of SAHA decreased biofilm formation for 24 h on PLA, SR, RG, Chicken skin, and eggshell by 3.98, 3.84, 4.11, 2.86 and 3.01 log ( < 0.05), respectively. In addition, the initial rate of bacterial biofilm formation was higher on chicken skin than on other surfaces, but the inhibitory effect was reduced. Consistent with this conclusion, virulence genes expression ( and ) and quorum-sensing (QS) gene () was considerably downregulated at sub-MIC of SAHA. SAHA has potential as an anti-biofilm agent against enterica serotype Kentucky biofilm, mostly by inhibiting virulence and quorum-sensing gene expression, proving the histone deacetylase inhibitor could be used to control food-borne biofilms in the food industry.
Topics: Biofilms; Salmonella enterica; Vorinostat; Virulence; Serogroup; Histone Deacetylase Inhibitors; Kentucky; Rubber; Quorum Sensing; Polyesters
PubMed: 37580896
DOI: 10.1080/08927014.2023.2242263 -
Research in Veterinary Science Oct 2019To explore the effect of epigenetic modification on the differentiation of goat adipose-derived stem cells in vitro, we used two common epigenetic modification...
To explore the effect of epigenetic modification on the differentiation of goat adipose-derived stem cells in vitro, we used two common epigenetic modification inhibitors, trichostatin A and vorinostat, to treat cashmere goat adipose-derived stem cells and induce adipocyte differentiation. The results showed that trichostatin A and vorinostat changed the relative amounts of H3K9 acetylation and dimethylation in the upstream sequence of PPARG, increased peroxisome proliferator-activated receptor gamma (PPARG) transcription before differentiation and then promoted adipocyte differentiation, and regulated the expression of adipocyte-specific genes. We conclude that adipocyte differentiation is regulated dynamically by different histone modifications. The areas of acetylation and demethylation changed by trichostatin A and vorinostat are the basis for further research on the mechanism of PPARG promoter to regulate adipocytes differentiation and provide research theroies for using adipose-derived stem cells as donor to produce transgenic animals to improve meat quality improvement.
Topics: Acetylation; Adipocytes; Adipogenesis; Animals; Epigenesis, Genetic; Goats; Histone Deacetylase Inhibitors; Hydroxamic Acids; Methylation; PPAR gamma; Promoter Regions, Genetic; Stem Cells; Vorinostat
PubMed: 31610471
DOI: 10.1016/j.rvsc.2019.09.002 -
Pharmacological Research Jan 2019There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective,...
There is currently no satisfactory treatment for visceral leishmaniasis; the disease is thus in desperate need of novel drugs. The ideal candidate should be effective, safe, affordable, and administered via the oral route. Histone deacetylases (HDACs) are involved in silencing critical regulatory pathways, including pro-apoptotic programs, and represent potential therapeutic targets for pharmacological interventions. O-alkyl hydroxamates have traditionally been considered to exert no effect on mammal HDACs. The aim of this study was to evaluate the effect of MDG, a SAHA derivative of the O-alkyl hydroxamate family with no activity on human histone deacetylase enzymes, on the visceral leishmaniasis causative agents and in a murine model of the disease. The effects of vorinostat, tubacin and valproic acid (well-known mammal HDAC inhibitors) on the parasite were also evaluated. MDG was found to be highly active against Leishmania infantum and L. donovani intracellular amastigotes in vitro but not against the promastigote stage. In contrast, vorinostat, tubacin and valproic acid showed no activity against the parasite. Assays investigating hERG and Cav1.2 channels in vitro found no evidence of MDG-driven cardiotoxicity. MDG showed neither hepatotoxicity nor mutagenicity, nor did it exert activity on cytochrome P450 enzymes. MDG was adsorbed onto gold nanoparticles for the in vivo experiments, performed on infected Balb/c mice. MDG was effective at reducing the parasite load in major target tissues (bone marrow, spleen and liver) in more than 70% at 25 mg/kg through both the oral and intraperitoneal route, proving more active than the reference compounds (meglumine antimoniate, MA) without showing toxicity. In addition, the combination of MDG and MA was very effective.
Topics: Administration, Oral; Anilides; Animals; Antiprotozoal Agents; Drug Delivery Systems; Female; Gold; Histone Deacetylase Inhibitors; Hydroxamic Acids; Leishmania infantum; Leishmaniasis, Visceral; Mice, Inbred BALB C; Mice, Inbred ICR; Nanoparticles; Valproic Acid; Vorinostat
PubMed: 30503838
DOI: 10.1016/j.phrs.2018.11.039 -
Haematologica Feb 2024Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable...
Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma [NHL]). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level [DL]1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome [SJS]), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).
Topics: Humans; Vorinostat; Neoplasm Recurrence, Local; Lymphoma, Non-Hodgkin; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Follicular; Antibodies, Monoclonal, Humanized
PubMed: 37470137
DOI: 10.3324/haematol.2023.283002 -
Journal of Drug Targeting Mar 2019Non-viral gene delivery is an attractive approach for the treatment of many diseases including cancer, benefiting from its safety and large-scale production concerns....
Non-viral gene delivery is an attractive approach for the treatment of many diseases including cancer, benefiting from its safety and large-scale production concerns. However, the relatively low transfection efficacy compared with viral vectors restricts the clinical applications of non-viral gene vectors. Reactive oxygen species (ROS) triggered charge reversal polymers (named B-PDEAEA) presented improved transfection efficacy, because of fast release of plasmid DNA responding to enhanced oxidative stress in cancer cells. But inadequate dissociation can still occur owing to the insufficient intracellular ROS generation. Here, we report SAHA (vorinostat), which is a clinical histone deacetylase inhibitor and anticancer drug, induces the ROS accumulation in cancer cells, and facilitates the charge reversal process of B-PDEAEA and the cellular dissociation of the delivered gene from the vectors. As a result, SAHA remarkably increases the gene transfection efficacy in an ROS-dependent manner. Importantly, SAHA synergizes with B-PDEAEA mediated therapeutic gene TNF-related apoptosis-inducing ligand (TRAIL) delivery in inducing apoptosis of cancer cells. These findings support the first concept of improving the gene delivery efficacy of stimuli-responsive vectors through upregulating the cellular ROS via an FDA approved anticancer agent. Additionally, combination of SAHA and TRAIL gene therapy could be a potential strategy for cancer treatment.
Topics: A549 Cells; Animals; Antineoplastic Agents; Apoptosis; Combined Modality Therapy; Gene Transfer Techniques; Genetic Therapy; HeLa Cells; Histone Deacetylase Inhibitors; Humans; Mice; Neoplasms; Oxidative Stress; Polymers; Reactive Oxygen Species; TNF-Related Apoptosis-Inducing Ligand; Transfection; Up-Regulation; Vorinostat
PubMed: 30188217
DOI: 10.1080/1061186X.2018.1519028