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Journal of Biochemical and Molecular... Sep 2021Osteoarthritis (OA) is a common joint disease that ultimately causes physical disability and imposes an economic burden on society. Cartilage destruction plays a key...
Osteoarthritis (OA) is a common joint disease that ultimately causes physical disability and imposes an economic burden on society. Cartilage destruction plays a key role in the development of OA. Vorinostat is an oral histone deacetylase (HDAC) inhibitor and has been used for the treatment of T-cell lymphoma. Previous studies have reported the anti-inflammatory effect of HDAC inhibitors in both in vivo and in vitro models. However, it is unknown whether vorinostat exerts a protective effect in OA. In this study, our results demonstrate that treatment with vorinostat prevents interleukin 1α (IL-1α)-induced reduction of type II collagen at both gene and protein levels. Treatment with vorinostat reduced the IL-1α-induced production of mitochondrial reactive oxygen species (ROS) in T/C-28a2 cells. Additionally, vorinostat rescued the IL-1α-induced decrease in the expression of the collagen type II a1 (Col2a1) gene and the expression of Sry-related HMG box 9 (SOX-9). Importantly, we found that vorinostat inhibited the expression of matrix metalloproteinase-13 (MMP-13), which is responsible for the degradation of type II collagen. Furthermore, vorinostat suppressed the expression of E74-like factor 3 (ELF3), which is a key transcription factor that plays a pivotal role in the IL-1α-induced reduction of type II collagen. Also, the overexpression of ELF3 abolished the protective effects of vorinostat against IL-1α-induced loss of type 2 collagen by inhibiting the expression of SOX-9 whilst increasing the expression of MMP-13. In conclusion, our findings suggest that vorinostat might prevent cartilage destruction by rescuing the reduction of type II collagen, mediated by the suppression of ELF3.
Topics: Cell Line; Chondrocytes; Collagen Type II; DNA-Binding Proteins; Gene Expression Regulation; Humans; Interleukin-1alpha; Proto-Oncogene Proteins c-ets; Transcription Factors; Vorinostat
PubMed: 34250664
DOI: 10.1002/jbt.22844 -
BMB Reports Jul 2023Natural killer (NK) cells are an essential part of the innate immune system that helps control infections and tumors. Recent studies have shown that Vorinostat, a...
Natural killer (NK) cells are an essential part of the innate immune system that helps control infections and tumors. Recent studies have shown that Vorinostat, a histone deacetylase (HDAC) inhibitor, can cause significant changes in gene expression and signaling pathways in NK cells. Since gene expression in eukaryotic cells is closely linked to the complex three-dimensional (3D) chromatin architecture, an integrative analysis of the transcriptome, histone profiling, chromatin accessibility, and 3D genome organization is needed to gain a more comprehensive understanding of how Vorinostat impacts transcription regulation of NK cells from a chromatin-based perspective. The results demonstrate that Vorinostat treatment reprograms the enhancer landscapes of the human NK-92 NK cell line while overall 3D genome organization remains largely stable. Moreover, we identified that the Vorinostat-induced RUNX3 acetylation is linked to the increased enhancer activity, leading to elevated expression of immune response-related genes via long-range enhancerpromoter chromatin interactions. In summary, these findings have important implications in the development of new therapies for cancer and immune-related diseases by shedding light on the mechanisms underlying Vorinostat's impact on transcriptional regulation in NK cells within the context of 3D enhancer network. [BMB Reports 2023; 56(7): 398-403].
Topics: Humans; Vorinostat; Acetylation; Hydroxamic Acids; Histone Deacetylase Inhibitors; Chromatin; Killer Cells, Natural; Cell Line, Tumor
PubMed: 37220907
DOI: 10.5483/BMBRep.2023-0044 -
Colloids and Surfaces. B, Biointerfaces Oct 2020Histonedeacetylase inhibitor (HDACi) has great potential in targeted antitumor therapy by inhibiting tumor migration, invasion, and metastasis. As one of the typical...
Histonedeacetylase inhibitor (HDACi) has great potential in targeted antitumor therapy by inhibiting tumor migration, invasion, and metastasis. As one of the typical HDACis, vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) was approved as a therapeutic agent for cancer therapy, however, challenges remain due to their poor solubility, short half-life and low efficiency in cellular penetration. Considering the disadvantages of usual drug carriers, folate and vorinostat bound BSA nanogel (FVBN)was fabricated to implement higher solubility, stability, cellular uptake, and lipase-responsive release. With good dispersion and stability, FVBN significantly increased the cellular uptake of vorinostat through folate-mediated endocytosis. FVBN exhibited comparable cytotoxicity with free SAHA, and the growth of tumor cells was blocked in G1/G0 phase just like SAHA performed in cell cycle arrest tests. Moreover, FVBN not only effectively inhibited the growth of melanoma but also observably prevented pulmonary metastasis of melanoma. In the experiment against nude mice bearing solid ovarian cancer, FVBN showed excellent antitumor effect without liver damage, demonstrating the superiority of gelated and inner-lysosome triggered release strategies to the free SAHA, and it is promising to expand the scope of application of HDACi in clinical cancer therapy.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Cell Proliferation; Female; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lysosomes; Mice; Mice, Nude; Vorinostat
PubMed: 32535244
DOI: 10.1016/j.colsurfb.2020.111144 -
Blood Oct 2017
Topics: Graft vs Host Disease; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Vorinostat
PubMed: 29025718
DOI: 10.1182/blood-2017-08-802249 -
Cancer Medicine Jan 2018Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and...
Oxaliplatin-based systemic chemotherapy has been proposed to have efficacy in hepatocellular carcinoma (HCC). We investigated the combination of vorinostat and oxaliplatin for possible synergism in HCC cells. SMMC7721, BEL7402, and HepG2 cells were treated with vorinostat and oxaliplatin. Cytotoxicity assay, tumorigenicity assay in vitro, cell cycle analysis, apoptosis analysis, western blot analysis, animal model study, immunohistochemistry, and quantitative PCR were performed. We found that vorinostat and oxaliplatin inhibited the proliferation of SMMC7721, BEL7402, and HepG2 cells. The combination index (CI) values were all <1, and the dose-reduction index values were all greater than 1 in the three cell lines, indicating a synergistic effect of combination of the two agents. Coadministration of vorinostat and oxaliplatin induced G2/M phase arrest, triggered caspase-dependent apoptosis, and decreased tumorigenicity both in vitro and in vivo. Vorinostat suppressed the expression of BRCA1 induced by oxaliplatin. In conclusion, cotreatment with vorinostat and oxaliplatin exhibited synergism in HCC cells. The combination inhibited cell proliferation and tumorigenicity both in vitro and in vivo through induction of cell cycle arrest and apoptosis. Our results predict that a combination of vorinostat and oxaliplatin may be useful in the treatment of advanced HCC.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinogenesis; Carcinoma, Hepatocellular; Cell Cycle Checkpoints; Cell Proliferation; Drug Synergism; Hep G2 Cells; Humans; Liver Neoplasms; Mice; Oxaliplatin; Treatment Outcome; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 29239146
DOI: 10.1002/cam4.1278 -
International Journal of Molecular... Apr 2023Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF...
Mycosis fungoides (MF) is the most common form of cutaneous T-cell lymphoma (CTCL) and is characterized by epidermotrophism of malignant CD4+ T-lymphocytes. When MF advances to a recurrent stage, patients require treatment with systemic therapies such as vorinostat, a histone deacetylase inhibitor. While vorinostat has been shown to exhibit anti-tumor activity in MF, its exact molecular mechanism has yet to be fully discerned. In the present study, we examined the transcriptomic and proteomic profiles of vorinostat treatment in two MF cell lines, Myla 2059 and HH. We find that vorinostat downregulates CTLA-4, CXCR4, and CCR7 in both cell lines, but its effect on several key pathways differs between the two MF cell lines. For example, vorinostat upregulates CCL5, CCR5, and CXCL10 expression in Myla cells but downregulates CCL5 and CXCL10 expression in HH cells. Furthermore, vorinostat upregulates IFN-γ and IL-23 signaling and downregulates IL-6, IL-7, and IL-15 signaling in Myla cells but does not affect these pathways in HH cells. Although Myla and HH represent established MF cell lines, their distinct tumor origin from separate patients demonstrates that inherent phenotypic variations within the disease persist, underscoring the importance of using a variety of MF cells in the preclinical development of MF therapeutics.
Topics: Humans; Vorinostat; Proteomics; Mycosis Fungoides; Lymphoma, T-Cell, Cutaneous; Skin Neoplasms
PubMed: 37175780
DOI: 10.3390/ijms24098075 -
Molecular Cancer Therapeutics Aug 2019The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer...
The 5-fluorouracil/cisplatin (5FU/CDDP) combination is one of the most widely used treatment options for several solid tumors. However, despite good anticancer responses, this regimen is often associated with high toxicity and treatment resistance. In our study, we evaluated whether the histone deacetylase inhibitor (HDACi), vorinostat, may induce synergistic antitumor and proapoptotic effects in combination with 5FU/CDDP in squamous cancer cell models. We demonstrated in cancer cell lines, including the intrinsic CDDP-resistant Cal27 cells, that simultaneous exposure to equitoxic doses of vorinostat plus 5FU/CDDP results in strong synergistic antiproliferative and proapoptotic effects related to cell-cycle perturbation and DNA damage induction. These effects were confirmed in both orthotopic and heterotopic xenograft mouse models of Cal27 cells. Mechanistically, vorinostat reverted 5FU/CDDP-induced EGFR phosphorylation and nuclear translocation, leading to the impairment of nuclear EGFR noncanonical induction of genes such as thymidylate synthase and cyclin D1. These effects were exerted by vorinostat, at least in part, by increasing lysosomal-mediated EGFR protein degradation. Moreover, vorinostat increased platinum uptake and platinated DNA levels by transcriptionally upregulating the CDDP influx channel copper transporter 1 (CTR1). Overall, to our knowledge, this study is the first to demonstrate the ability of vorinostat to inhibit two well-known mechanisms of CDDP resistance, EGFR nuclear translocation and CTR1 overexpression, adding new insight into the mechanism of the synergistic interaction between HDACi- and CDDP-based chemotherapy and providing the rationale to clinically explore this combination to overcome dose-limiting toxicity and chemotherapy resistance.
Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; Copper Transporter 1; DNA Damage; Disease Models, Animal; Drug Synergism; ErbB Receptors; Female; Fluorouracil; Mice; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 31189612
DOI: 10.1158/1535-7163.MCT-18-1117 -
Toxicology Aug 2020Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects...
Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.
Topics: Animals; Antineoplastic Agents; Apoptosis; Bone Marrow Cells; Chromosome Aberrations; Comet Assay; DNA Methylation; DNA Repair; Dose-Response Relationship, Drug; Down-Regulation; Male; Mice; Oxidative Stress; Vorinostat
PubMed: 32512035
DOI: 10.1016/j.tox.2020.152507 -
Biological Chemistry Mar 2021Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a...
Triple-negative breast cancers (TNBC) that produce nitric oxide (NO) are more aggressive, and the expression of the inducible form of nitric oxide synthase (NOS2) is a negative prognostic indicator. In these studies, we set out to investigate potential therapeutic strategies to counter the tumor-permissive properties of NO. We found that exposure to NO increased proliferation of TNBC cells and that treatment with the histone deacetylase inhibitor Vorinostat (SAHA) prevented this proliferation. When histone acetylation was measured in response to NO and/or SAHA, NO significantly decreased acetylation on histone 3 lysine 9 (H3K9ac) and SAHA increased H3K9ac. If NO and SAHA were sequentially administered to cells (in either order), an increase in acetylation was observed in all cases. Mechanistic studies suggest that the "deacetylase" activity of NO does not involve -nitrosothiols or soluble guanylyl cyclase activation. The observed decrease in histone acetylation by NO required the interaction of NO with cellular iron pools and may be an overriding effect of NO-mediated increases in histone methylation at the same lysine residues. Our data revealed a novel pathway interaction of Vorinostat and provides new insight in therapeutic strategy for aggressive TNBCs.
Topics: Acetylation; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors; Histones; Humans; Nitric Oxide; Triple Negative Breast Neoplasms; Vorinostat
PubMed: 33938179
DOI: 10.1515/hsz-2020-0323 -
European Review For Medical and... Feb 2023Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient....
OBJECTIVE
Breast cancer (BC) is the most common type of cancer in females worldwide. Various approaches were proposed to treat the disease, with no sole agent proved efficient. Thus, understanding the molecular mechanisms of different drugs became mandatory. The present study aimed at evaluating the role of erlotinib (ERL) and vorinostat (SAHA) in inducing apoptosis in breast cancer cells. The role of these drugs was assessed also on the expression profile of some cancer-related genes; PTEN, P21, TGF, and CDH1.
MATERIALS AND METHODS
In the present study, breast cancer cells (MCF-7) and MDA-MB-231 along with human amniotic cells (WISH) were treated with two concentrations (50, and 100 µM) of erlotinib (ERL) and vorinostat (as known as SAHA) for 24 h. Cells were harvested for downstream analysis. DNA content and apoptosis were analyzed by flow cytometer, and qPCR was performed to assess the expression of different cancer-related genes.
RESULTS
The results indicated that ERL and SAHA arrested both breast cancer cells at the G2/M phase after 24 h compared to normal cells and control. For apoptosis, BC cells showed an elevated level of total apoptosis (early and late) increasing the concentrations of the two applied drugs, with the most effective concentration of ERL at 100 µM in the 24-h treatment. In the control cells, SAHA was proved to be the most effective drug at a concentration of 100 µM with a percentage of apoptosis ranging from 1.7-12% in the 24-h treatment. Necrosis also was dose-dependent in the two breast cancer cell lines used. We further evaluated the expression profiles of PTEN, P21, TGF-β, and CDH1. In MCF-7, data indicated that for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was ERL at 100 µM. A similar profile was observed in MDA-MB-232, where for TGF-β, PTEN, and P21, the most effective treatment was SAHA at a concentration of 100 µM, while for CDH1, the most effective concentration was SAHA at 50 µM.
CONCLUSIONS
Our results shed some light on the role of ERL and SAHA in regulating the expression of cancer-related genes, though these data need further investigation.
Topics: Female; Humans; Erlotinib Hydrochloride; PTEN Phosphohydrolase; Transcriptional Activation; Up-Regulation; Vorinostat; Breast Neoplasms; Cell Line, Tumor; Cell Cycle Checkpoints
PubMed: 36876690
DOI: 10.26355/eurrev_202302_31391