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Frontiers in Immunology 2023Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy,... (Review)
Review
Breast cancer is one of the common malignancies with poor prognosis worldwide. The treatment of breast cancer patients includes surgery, radiation, hormone therapy, chemotherapy, targeted drug therapy and immunotherapy. In recent years, immunotherapy has potentiated the survival of certain breast cancer patients; however, primary resistance or acquired resistance attenuate the therapeutic outcomes. Histone acetyltransferases induce histone acetylation on lysine residues, which can be reversed by histone deacetylases (HDACs). Dysregulation of HDACs mutation and abnormal expression contributes to tumorigenesis and tumor progression. Numerous HDAC inhibitors have been developed and exhibited the potent anti-tumor activity in a variety of cancers, including breast cancer. HDAC inhibitors ameliorated immunotherapeutic efficacy in cancer patients. In this review, we discuss the anti-tumor activity of HDAC inhibitors in breast cancer, including dacinostat, belinostat, abexinostat, mocetinotat, panobinostat, romidepsin, entinostat, vorinostat, pracinostat, tubastatin A, trichostatin A, and tucidinostat. Moreover, we uncover the mechanisms of HDAC inhibitors in improving immunotherapy in breast cancer. Furthermore, we highlight that HDAC inhibitors might be potent agents to potentiate immunotherapy in breast cancer.
Topics: Humans; Female; Histone Deacetylases; Histone Deacetylase Inhibitors; Breast Neoplasms; Vorinostat; Immunotherapy
PubMed: 36969235
DOI: 10.3389/fimmu.2023.1164514 -
International Immunopharmacology Jul 2023Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as... (Review)
Review
Immunotherapy based on immune checkpoint inhibitors (ICIs) has revolutionized treatment strategies in multiple types of cancer. However, the resistance and relapse as associated with the extreme complexity of cancer-immunity interactions remain a major challenge to be resolved. Owing to the epigenome plasticity of cancer and immune cells, a growing body of evidence has been presented indicating that epigenetic treatments have the potential to overcome current limitations of immunotherapy, thus providing a rationalefor the combination of ICIs with epigenetic agents (epidrugs). In this review, we first make an overview about the epigenetic regulations in tumor biology and immunodevelopment. Subsequently, a diverse array of inhibitory agents under investigations targeted epigenetic modulators (Azacitidine, Decitabine, Vorinostat, Romidepsin, Belinostat, Panobinostat, Tazemetostat, Enasidenib and Ivosidenib, etc.) and immune checkpoints (Atezolizmab, Avelumab, Cemiplimab, Durvalumb, Ipilimumab, Nivolumab and Pembrolizmab, etc.) to increase anticancer responses were described and the potential mechanisms were further discussed. Finally, we summarize the findings of clinical trials and provide a perspective for future clinical studies directed at investigating the combination of epidrugs with ICIs as a treatment for cancer.
Topics: Humans; Immune Checkpoint Inhibitors; Neoplasms; Nivolumab; Ipilimumab; Immunotherapy
PubMed: 37276826
DOI: 10.1016/j.intimp.2023.110417 -
Chonnam Medical Journal Jan 2016Histone deacetylases (HDACs) are epigenetic regulators that regulate the histone tail, chromatin conformation, protein-DNA interaction, and even transcription. HDACs are... (Review)
Review
Histone deacetylases (HDACs) are epigenetic regulators that regulate the histone tail, chromatin conformation, protein-DNA interaction, and even transcription. HDACs are also post-transcriptional modifiers that regulate the protein acetylation implicated in several pathophysiologic states. HDAC inhibitors have been highlighted as a novel category of anti-cancer drugs. To date, four HDAC inhibitors, Vorinostat, Romidepsin, Panobinostat, and Belinostat, have been approved by the United States Food and Drug Administration. Principally, these HDAC inhibitors are used for hematologic cancers in clinic with less severe side effects. Clinical trials are continuously expanding to address other types of cancer and also nonmalignant diseases. HDAC inhibition also results in beneficial outcomes in various types of neurodegenerative diseases, inflammation disorders, and cardiovascular diseases. In this review, we will briefly discuss 1) the roles of HDACs in the acquisition of a cancer's phenotype and the general outcome of the HDAC inhibitors in cancer, 2) the functional relevance of HDACs in cardiovascular diseases and the possible therapeutic implications of HDAC inhibitors in cardiovascular disease.
PubMed: 26865995
DOI: 10.4068/cmj.2016.52.1.1 -
The Journal of Investigative Dermatology Dec 2021Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor...
Sézary syndrome is an aggressive and disseminated form of cutaneous T-cell lymphoma associated with dismal prognosis in which the histone deacetylase inhibitor romidepsin has shown remarkable activity as a single agent. However, clinical responses to romidepsin are typically transient, highlighting the need for more effective therapies. In this study, we show synergistic antilymphoma effects of romidepsin in combination with mechlorethamine, an alkylating agent, in cutaneous T-cell lymphoma cell lines and primary samples with strong antitumor effects in an in vivo model of Sézary syndrome. Mechanistically, gene expression profiling points to abrogation of Jak/signal transducer and activator of transcription (STAT) signaling as an important mediator of this interaction. Consistently, the combination of mechlorethamine plus romidepsin resulted in downregulation of STAT5 phosphorylation in romidepsin-sensitive cell lines and primary Sézary syndrome samples, but not in romidepsin-resistant tumors. Moreover, in further support of Jak/STAT signaling as a modulator of romidepsin activity in cutaneous T-cell lymphoma, treatment with romidepsin in combination with Jak inhibitors resulted in markedly increased therapeutic responses. Overall, these results support a role for romidepsin plus mechlorethamine in combination in the treatment of cutaneous T-cell lymphoma and uncover a previously unrecognized role for Jak/STAT signaling in the response to romidepsin and romidepsin-based combination therapies in Sézary syndrome.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line, Tumor; Depsipeptides; Drug Synergism; Humans; Janus Kinase Inhibitors; Lymphoma, T-Cell, Cutaneous; Mechlorethamine; Mice; STAT Transcription Factors; Signal Transduction; Skin Neoplasms
PubMed: 34089720
DOI: 10.1016/j.jid.2021.04.023 -
Nutrients Jun 2018Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an... (Review)
Review
Cancer initiation and progression are the result of genetic and/or epigenetic alterations. Acetylation-mediated histone/non-histone protein modification plays an important role in the epigenetic regulation of gene expression. Histone modification is controlled by the balance between histone acetyltransferase and (HAT) and histone deacetylase (HDAC) enzymes. Imbalance between the activities of these two enzymes is associated with various forms of cancer. Histone deacetylase inhibitors (HDACi) regulate the activity of HDACs and are being used in cancer treatment either alone or in combination with other chemotherapeutic drugs/radiotherapy. The Food and Drug Administration (FDA) has already approved four compounds, namely vorinostat, romidepsin, belinostat, and panobinostat, as HDACi for the treatment of cancer. Several other HDACi of natural and synthetic origin are under clinical trial for the evaluation of efficiency and side-effects. Natural compounds of plant, fungus, and actinomycetes origin, such as phenolics, polyketides, tetrapeptide, terpenoids, alkaloids, and hydoxamic acid, have been reported to show potential HDAC-inhibitory activity. Several HDACi of natural and dietary origin are butein, protocatechuic aldehyde, kaempferol (grapes, green tea, tomatoes, potatoes, and onions), resveratrol (grapes, red wine, blueberries and peanuts), sinapinic acid (wine and vinegar), diallyl disulfide (garlic), and zerumbone (ginger). HDACi exhibit their antitumor effect by the activation of cell cycle arrest, induction of apoptosis and autophagy, angiogenesis inhibition, increased reactive oxygen species generation causing oxidative stress, and mitotic cell death in cancer cells. This review summarizes the HDACs classification, their aberrant expression in cancerous tissue, structures, sources, and the anticancer mechanisms of HDACi, as well as HDACi that are either FDA-approved or under clinical trials.
Topics: Acetylation; Animals; Antineoplastic Agents; Drug Discovery; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Molecular Targeted Therapy; Mutation; Neoplasms; Substrate Specificity
PubMed: 29882797
DOI: 10.3390/nu10060731 -
Frontiers in Immunology 2022The viral transactivator Tax plays a key role in HTLV-1 reactivation and infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate...
The viral transactivator Tax plays a key role in HTLV-1 reactivation and infection. Previous approaches focused on the histone deacetylase inhibitor (HDACi) Valproate as a latency-reversing agent to boost Tax expression and expose infected cells to the host's immune response. However, following treatment with Valproate proviral load decreases in patients with HAM/TSP were only transient. Here, we hypothesize that other compounds, including more potent and selective HDACi, might prove superior to Valproate in manipulating Tax expression. Thus, a panel of HDACi (Vorinostat/SAHA/Zolinza, Panobinostat/LBH589/Farydak, Belinostat/PXD101/Beleodaq, Valproate, Entinostat/MS-275, Romidepsin/FK228/Istodax, and MC1568) was selected and tested for toxicity and potency in enhancing Tax expression. The impact of the compounds was evaluated in different model systems, including transiently transfected T-cells, chronically HTLV-1-infected T-cell lines, and freshly isolated PBMCs from HTLV-1 carriers . We identified the pan-HDACi Panobinostat and class I HDACi Romidepsin as particularly potent agents at raising Tax expression. qRT-PCR analysis revealed that these inhibitors considerably boost and Tax-target gene transcription. However, despite this significant increase in transcription and histone acetylation, protein levels of Tax were only moderately enhanced. In conclusion, these data demonstrate the ability of Panobinostat and Romidepsin to manipulate Tax expression and provide a foundation for further research into eliminating latently infected cells. These findings also contribute to a better understanding of conditions limiting transcription and translation of viral gene products.
Topics: Cell Line; Depsipeptides; Histone Deacetylase Inhibitors; Human T-lymphotropic virus 1; Humans; Panobinostat; T-Lymphocytes; Valproic Acid; Vorinostat
PubMed: 36052071
DOI: 10.3389/fimmu.2022.978800 -
Frontiers in Medicine 2019Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and... (Review)
Review
Mycosis fungoides (MF) and Sézary syndrome (SS) are the most common subtypes of cutaneous T-cell lymphoma. The majority of MF cases present with only patches and plaques and the lesions are usually limited to the skin. On the other hand, in some cases, patients show skin tumors or erythroderma followed by lymph node involvement and rarely visceral organ involvement. SS is a rare, aggressive cutaneous T-cell lymphoma marked by exfoliative erythroderma, lymphadenopathy, and leukemic blood involvement. Because patients with relapsed or refractory MF/SS display a poor prognosis and the current treatment options are characterized by high rates of relapse, there is unmet need for the efficient treatment. This review provides a discussion of the recent and future promising therapeutic approaches in the management of advanced MF/SS. These include mogamulizumab, brentuximab vedotin, alemtuzumab, immune checkpoint inhibitors, IPH4102 (anti-KIR3DL2 antibody), histone deacetylase inhibitors (vorinostat, romidepsin, panobinostat, belinostat, and resminostat), pralatrexate, forodesine, denileukin diftitox, duvelisib, lenalidomide, and everolimus.
PubMed: 31192214
DOI: 10.3389/fmed.2019.00116 -
Frontiers in Medicine 2021Peripheral T-cell lymphoma (PTCL) is an extensive class of biologically and clinically heterogeneous diseases with dismal outcomes. The histone deacetylase inhibitor...
Peripheral T-cell lymphoma (PTCL) is an extensive class of biologically and clinically heterogeneous diseases with dismal outcomes. The histone deacetylase inhibitor (HDACi) romidepsin was approved for relapsed and refractory (R/R-PTCL) in 2011. This meta-analysis was performed to assess the efficacy and safety of romidepsin in PTCL. We searched for articles on the HDAC inhibitor romidepsin in the treatment of PTCL in Embase, Web of Science, and PubMed. The methodology is further detailed in PROSPERO (CRD42020213651, CRD42020213553). The 2-year overall survival (OS), 2-year progression-free survival (PFS), and their corresponding to 95% confidence intervals (CIs) were measured. Besides, corresponding 95% CIs were pooled for the complete response (CR), partial response (PR), duration of response (DoR), and risk of adverse events (AEs). Eleven studies containing 388 patients were incorporated into the quantitative synthesis, of which R/R-PTCL patients were the dominant portion, accounting for 94.3% (366/388). For all studies, the CR rate was 20% (95% CI, 13-27%, random effects model), and the PR rate was 18% (95% CI, 12-25%, random effects model). The 2-year OS was 48% (95% CI, 38-59%, fixed effects model), and the 2-year PFS was 17% (95% CI, 13-21%, fixed effects model). There were no significant differences between romidepsin monotherapy and romidepsin plus additional drugs. Hematological toxicities, such as lymphopenia and granulocytopenia, remained the most continually happening grade 3 or higher AEs, accounting for 46 and 28%, respectively. None of the studies reported any drug-related mortality. Considering that most of the included patients had R/R-PTCL, the addition of romidepsin significantly enhance the efficacy. And AEs were tolerable as the grade 3/4 AEs in romidepsin monotherapy was 7% (95% CI, 6-8%). It is imperative to further expand the first-line application of romidepsin and carry out personalized therapy based on epigenomics, which will improve the survival of PTCL patients. https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213651 and https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020213553.
PubMed: 34805202
DOI: 10.3389/fmed.2021.732727 -
Blood Advances Aug 2018Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial...
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure.
Topics: Aged; Aged, 80 and over; Depsipeptides; Drug Resistance, Neoplasm; Female; Flow Cytometry; Histone Deacetylase Inhibitors; Humans; Male; Middle Aged; Sezary Syndrome; T-Lymphocytes; Vorinostat
PubMed: 30139925
DOI: 10.1182/bloodadvances.2018022608 -
American Journal of Cancer Research 2022Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its...
Uterine endometrial cancer (EC) incidence and deaths are on the rise. Hormone therapy, a traditional treatment regimen for this disease, uses progesterone and its synthetic analogue, progestin, to induce cell differentiation, apoptosis, and inhibition of invasion. This therapy is highly effective for progesterone receptor (PR) positive tumors in the short term. However, responsiveness decreases over time due to loss of PR expression; acquired resistance leads to treatment failure and poor prognosis. Primary resistance occurs in advanced, PR-negative tumors. Regardless, progestin therapy can be effective if the PR downregulation mechanism is reversed and if functional PR expression is restored. Using histone deacetylase inhibitors (HDACi), we inhibited cell proliferation in three EC cell lines and restored functional PR expression at the mRNA and protein levels. Two HDACi were tested using an endometrial xenograft tumor model: entinostat, an oral drug, and romidepsin, an IV drug. and studies support that entinostat decreased EC tumor growth, induced differentiation, and increased expression of the PR-targeted gene, PAEP. These findings supported the approval of a new NIH NCTN clinical trial, NRG-GY011, which concluded that dual treatment of MPA and entinostat, decreased expression of the proliferation marker, Ki67, but did not increase PR expression relative to single treatment with MPA in this short-term study. Therefore, a more potent HDACi, romidepsin, was investigated. Romidepsin treatment inhibited tumor growth and enhanced progestin treatment efficacy. More importantly, PR, PAEP, and KIAA1324 expressions were upregulated. Using a chromatin immunoprecipitation assay, we verified that HDACi can reverse PR downregulation mechanisms in mice models. Other potential drug efficacy markers, such as CD52, DLK1, GALNT9, and GNG2, were identified by transcriptome analysis and verified by q-PCR. Many of the upregulated drug efficacy markers predict favorable patient outcomes, while downregulated genes predict worse survival. Here, our current data suggests that romidepsin is a more potent HDACi that has the potential to achieve more robust upregulation of PR expression and may be a more promising candidate for future clinical trials.
PubMed: 36504895
DOI: No ID Found