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Proceedings of the National Academy of... Nov 2018Human papillomaviruses (HPVs) cause epithelial proliferative diseases. Persistent infection of the mucosal epithelia by the high-risk genotypes can progress to...
Human papillomaviruses (HPVs) cause epithelial proliferative diseases. Persistent infection of the mucosal epithelia by the high-risk genotypes can progress to high-grade dysplasia and cancers. Viral transcription and protein activities are intimately linked to regulation by histone acetyltransferases and histone deacetylases (HDACs) that remodel chromatin and regulate gene expression. HDACs are also essential to remodel and repair replicating chromatin to enable the progression of replication forks. As such, Vorinostat (suberoylanilide hydroximic acid), and other pan-HDAC inhibitors, are used to treat lymphomas. Here, we investigated the effects of Vorinostat on productive infection of the high-risk HPV-18 in organotypic cultures of primary human keratinocytes. HPV DNA amplifies in the postmitotic, differentiated cells of squamous epithelia, in which the viral oncoproteins E7 and E6 establish a permissive milieu by destabilizing major tumor suppressors, the pRB family proteins and p53, respectively. We showed that Vorinostat significantly reduced these E6 and E7 activities, abrogated viral DNA amplification, and inhibited host DNA replication. The E7-induced DNA damage response, which is critical for both events, was also compromised. Consequently, Vorinostat exposure led to DNA damage and triggered apoptosis in HPV-infected, differentiated cells, whereas uninfected tissues were spared. Apoptosis was attributed to highly elevated proapoptotic Bim isoforms that are known to be repressed by EZH2 in a repressor complex containing HDACs. Two other HDAC inhibitors, Belinostat and Panobinostat, also inhibited viral DNA amplification and cause apoptosis. We suggest that HDAC inhibitors are promising therapeutic agents to treat benign HPV infections, abrogate progeny virus production, and hence interrupt transmission.
Topics: Apoptosis; Bcl-2-Like Protein 11; Cells, Cultured; DNA Repair; DNA Replication; DNA, Viral; DNA-Binding Proteins; Histone Deacetylase Inhibitors; Histones; Human papillomavirus 18; Humans; Hydroxamic Acids; Keratinocytes; Mucous Membrane; Oncogene Proteins, Viral; Panobinostat; Papillomavirus Infections; Sulfonamides; Tumor Suppressor Protein p53; Vorinostat
PubMed: 30385631
DOI: 10.1073/pnas.1801156115 -
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 -
Biology of Blood and Marrow... Jan 2020Post-autologous stem cell transplantation (ASCT) maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma (MM). Effective and...
Post-autologous stem cell transplantation (ASCT) maintenance therapy with lenalidomide is standard of care for patients with multiple myeloma (MM). Effective and tolerable drug combinations may further enhance the clinical response post-ASCT. Vorinostat, a histone deacetylase inhibitor, induces antiproliferative and proapoptotic effects in patients with MM. We hypothesized that combination maintenance therapy would further prolong the clinical response achieved from transplantation. We previously reported that the combination of lenalidomide and vorinostat as maintenance post-ASCT was tolerable in 16 patients with MM. We now present the long-term follow up of these patients. Progression-free survival (PFS) and overall survival (OS) outcomes were characterized using the Kaplan-Meier method. Five patients (31%) had high-risk disease, and the median number of lines of therapy before ASCT was 1 (range, 1 to 5). With a median follow-up of 89.8 months from ASCT, the median PFS was 64.3 months (range, 21.7 months to not reached [NR]), and OS was not reached (median, 53.0 months to NR). At the time of this report, 5 patients remained on the study. The combination of vorinostat and lenalidomide as maintenance post-ASCT is tolerable and induces a durable response. A phase III randomized study of lenalidomide versus a combination with vorinostat is warranted.
Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Autografts; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Lenalidomide; Maintenance Chemotherapy; Male; Middle Aged; Multiple Myeloma; Survival Rate; Vorinostat
PubMed: 31518644
DOI: 10.1016/j.bbmt.2019.09.005 -
Blood Oct 2017The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity...
The oral histone deacetylase (HDAC) inhibitor (vorinostat) is safe and results in low incidence of acute graft-versus-host disease (GVHD) after reduced-intensity conditioning, related donor hematopoietic cell transplantation (HCT). However, its safety and efficacy in preventing acute GVHD in settings of heightened clinical risk that use myeloablative conditioning, unrelated donor (URD), and methotrexate are not known. We conducted a prospective, phase 2 study in this higher-risk setting. We enrolled 37 patients to provide 80% power to detect a significant difference in grade 2 to 4 acute GVHD of 50% compared with a reduction in target to 28%. Eligibility included adults with a hematological malignancy to receive myeloablative HCT from an available 8/8-HLA matched URD. Patients received GVHD prophylaxis with tacrolimus and methotrexate. Vorinostat (100 mg twice daily) was started on day -10 and continued through day +100 post-HCT. Median age was 56 years (range, 18-69 years), and 95% had acute myelogenous leukemia or high-risk myelodysplastic syndrome. Vorinostat was safe and tolerable. The cumulative incidence of grade 2 to 4 acute GVHD at day 100 was 22%, and for grade 3 to 4 it was 8%. The cumulative incidence of chronic GVHD was 29%; relapse, nonrelapse mortality, GVHD-free relapse-free survival, and overall survival at 1 year were 19%, 16%, 47%, and 76%, respectively. Correlative analyses showed enhanced histone (H3) acetylation in peripheral blood mononuclear cells and reduced interleukin 6 ( = .028) and GVHD biomarkers (Reg3, = .041; ST2, = .002) at day 30 post-HCT in vorinostat-treated subjects compared with similarly treated patients who did not receive vorinostat. Vorinostat for GVHD prevention is an effective strategy that should be confirmed in a randomized phase 3 study. This trial was registered at www.clinicaltrials.gov as #NCT01790568.
Topics: Acetylation; Acute Disease; Adolescent; Adult; Aged; Demography; Feasibility Studies; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histone Deacetylase Inhibitors; Histones; Humans; Hydroxamic Acids; Incidence; Male; Methotrexate; Middle Aged; Recurrence; Survival Analysis; Tacrolimus; Transplantation Conditioning; Unrelated Donors; Vorinostat; Young Adult
PubMed: 28784598
DOI: 10.1182/blood-2017-06-790469 -
BMC Cancer Nov 2016Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and...
BACKGROUND
Vorinostat, a histone deacetylase (HDAC) inhibitor, is a promising agent for cancer therapy. Combining vorinostat with cisplatin may relax the chromatin structure and facilitate the accessibility of cisplatin, thus enhancing its cytotoxicity. Studies have not yet investigated the effects of the combination of vorinostat and cisplatin on small cell lung cancer (SCLC).
METHODS
We first assessed the efficacy of vorinostat with etoposide/cisplatin (EP; triple combination) and then investigated the effects of cotreatment with vorinostat and cisplatin on H209 and H146 SCLC cell lines. The anticancer effects of various combinations were determined in terms of cell viability, apoptosis, cell cycle distribution, and vorinostat-regulated proteins. We also evaluated the efficacy of vorinostat/cisplatin combination in H209 xenograft nude mice.
RESULTS
Our data revealed that the triple combination engendered a significant reduction of cell viability and high apoptotic cell death. In addition, vorinostat combined with cisplatin enhanced cell growth inhibition, induced apoptosis, and promoted cell cycle arrest. We observed that the acetylation levels of histone H3 and α-tubulin were higher in combination treatments than in vorinostat treatment alone. Moreover, vorinostat reduced the expression of thymidylate synthase (TS), and TS remained inhibited after cotreament with cisplatin. Furthermore, an in vivo study revealed that the combination of vorinostat and cisplatin significantly inhibited tumor growth in xenograft nude mice (tumor growth inhibition T/C% = 20.5 %).
CONCLUSIONS
Combined treatments with vorinostat promote the cytotoxicity of cisplatin and induce the expression of vorinostat-regulated acetyl proteins, eventually enhancing antitumor effects in SCLC cell lines. Triple combinations with a low dosage of cisplatin demonstrate similar therapeutic effects. Such triple combinations, if applied clinically, may reduce the undesired adverse effects of cisplatin. The effects of the combination of vorinostat and cisplatin should be evaluated further before conducting clinical trials for SCLC treatment.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Line, Tumor; Cell Survival; Cisplatin; Disease Models, Animal; Drug Synergism; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Lung Neoplasms; Mice; Small Cell Lung Carcinoma; Vorinostat; Xenograft Model Antitumor Assays
PubMed: 27821078
DOI: 10.1186/s12885-016-2888-7 -
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 -
Blood Sep 2020
Topics: HIV Infections; Humans; Lymphoma; Lymphoma, Non-Hodgkin; Vorinostat
PubMed: 32957115
DOI: 10.1182/blood.2020006651 -
Cell Host & Microbe Jan 2018Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and... (Review)
Review
Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is life long. HIV persists during ART due to long-lived and proliferating latently infected CD4+ T cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.
Topics: Anti-HIV Agents; Bryostatins; CD4-Positive T-Lymphocytes; Depsipeptides; HIV Infections; HIV-1; Humans; Hydroxamic Acids; Indoles; Panobinostat; Phosphoinositide-3 Kinase Inhibitors; Proto-Oncogene Proteins c-bcl-2; Virus Activation; Virus Latency; Vorinostat
PubMed: 29324227
DOI: 10.1016/j.chom.2017.12.004 -
The Oncologist Oct 2020The cholangiocarcinoma community has truly lost a young, talented, bright star, Dr. Supriya Kumar “Shoop” Saha. Despite his passing, he continues to inspire the...
The cholangiocarcinoma community has truly lost a young, talented, bright star, Dr. Supriya Kumar “Shoop” Saha. Despite his passing, he continues to inspire the search for a cure.
Topics: Apoptosis; Cell Line, Tumor; Histone Deacetylase Inhibitors; Humans; Hydroxamic Acids; Vorinostat
PubMed: 32835448
DOI: 10.1634/theoncologist.2020-0710