• Cancer treatment
• Colorectal cancer
• DNA methylation
• Epidrugs
• Epigenetics
• Histone modifications

• Humans
• Colorectal Neoplasms/genetics
• Colorectal Neoplasms/drug therapy
• Epigenesis, Genetic/drug effects
• DNA Methylation/drug effects
• Immunotherapy/methods
• Epigenomics/methods
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Gene Expression Regulation, Neoplastic/drug effects

• Cancer-associated fibroblasts
• Channelopathy
• Hypoxia
• Lidocaine
• Metastasis
• Tumours
• Voltage-gated sodium channel

• Humans
• Voltage-Gated Sodium Channels/metabolism
• Neoplasms/metabolism
• Phenotype
• Sodium/metabolism
• Tumor Microenvironment

• MR/X018067/1 Medical Research Council

• RNA-seq
• esophageal cancer
• fatty acids
• interaction networks
• membrane proteins

• Breast tumours
• CLINICAL PHARMACOLOGY
• Epilepsy
• ONCOLOGY

• Humans
• Anti-Arrhythmia Agents/therapeutic use
• Anticonvulsants/therapeutic use
• Electronics
• Primary Health Care
• Retrospective Studies
• Neoplasms/drug therapy
• Sodium Channel Blockers/therapeutic use

• Wellcome Trust
• 25922 Cancer Research UK
• 30380 Cancer Research UK
• G1000508 Medical Research Council
• Centre for Future Health at the University of York

Although in the last decades the clinical outcome of cancer patients considerably improved, the major drawbacks still associated with chemotherapy are the unwanted side effects and the development of drug resistance. Therefore, a continuous effort in trying to discover new tumor markers, possibly of diagnostic, prognostic and therapeutic value, is being made. This review is aimed at highlighting the anti-tumor activity that several antiepileptic drugs (AEDs) exert in breast, prostate and other types of cancers, mainly focusing on their ability to block the voltage-gated Na⁺ and Ca⁺⁺ channels, as well as to inhibit the activity of histone deacetylases (HDACs), all well-documented tumor markers and/or molecular targets. The existence of additional AEDs molecular targets is highly suspected. Therefore, the repurposing of already available drugs as adjuvants in cancer treatment would have several advantages, such as reductions in dose-related toxicity CVs will be sent in a separate mail to the indicated address of combined treatments, lower production costs, and faster approval for clinical use.

Cancer is a major health burden worldwide. Although the plethora of molecular targets identified in the last decades and the deriving developed treatments, which significantly improved patients’ outcome, the occurrence of resistance to therapies remains the major cause of relapse and mortality. Thus, efforts in identifying new markers to be exploited as molecular targets in cancer therapy are needed. This review will first give a glance on the diagnostic and therapeutic significance of histone deacetylase (HDAC) and voltage gated ion channels (VGICs) in cancer. Nevertheless, HDAC and VGICs have also been reported as molecular targets through which antiepileptic drugs (AEDs) seem to exert their anticancer activity. This should be claimed as a great advantage. Indeed, due to the slowness of drug approval procedures, the attempt to turn to off-label use of already approved medicines would be highly preferable. Therefore, an updated and accurate overview of both preclinical and clinical data of commonly prescribed AEDs (mainly valproic acid, lamotrigine, carbamazepine, phenytoin and gabapentin) in breast, prostate, brain and other cancers will follow. Finally, a glance at the emerging attempt to administer AEDs by means of opportunely designed drug delivery systems (DDSs), so to limit toxicity and improve bioavailability, is also given.

• HDAC inhibitors
• adjuvant anti-cancer therapy
• antiepileptic drugs
• cancer
• carbamazepine
• drug repositioning
• gabapentin
• lamotrigine
• phenytoin
• valproic acid
• voltage gated calcium channels
• voltage gated sodium channels

• HDAC inhibitors (HDACi)
• Histone deacetylase (HDAC)
• breast cancer
• ovarian cancer
• prostate cancer

• Androgen Receptor (AR)
• Lineage plasticity
• Neuroendocrine prostate cancer (NEPC)
• epigenetics
• transdifferentiation

• Androgen Antagonists/therapeutic use
• Carcinoma, Neuroendocrine/pathology
• Epigenesis, Genetic
• Humans
• Male
• Prostate/pathology
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/genetics
• Prostatic Neoplasms/metabolism
• Receptors, Androgen/genetics
• Receptors, Androgen/metabolism

• R01 CA251245 NCI NIH HHS
• T32 CA180984 NCI NIH HHS
• T32 CA009676 NCI NIH HHS
• P50 CA186786 NCI NIH HHS
• T32 CA009357 NCI NIH HHS
• National Cancer Institute
• U.S. Department of Defense

• Cancer stem cells
• cancer
• drug resistance
• epigenetics

• Drug Resistance, Neoplasm/genetics
• Epigenesis, Genetic/genetics
• Epithelial-Mesenchymal Transition/genetics
• Humans
• Neoplasm Recurrence, Local/pathology
• Neoplastic Stem Cells/pathology
• Signal Transduction/genetics
• Tumor Microenvironment/genetics

The initiation of prostate cancer has been long associated with DNA copy-number alterations, the loss of specific chromosomal regions and gene fusions, and driver mutations, especially those of the Androgen Receptor. Non-mutational events, particularly DNA and RNA epigenetic dysregulation, are emerging as key players in tumorigenesis. In this review we summarize the molecular changes linked to epigenetic and epitranscriptomic dysregulation in prostate cancer and the role that alterations to DNA and RNA modifications play in the initiation and progression of prostate cancer.

• DNA methylation
• RNA modifications
• epigenetics
• epitranscriptomics
• histone modifications
• novel therapeutics
• prostate cancer

• Carcinogenesis/genetics
• Epigenesis, Genetic
• Epigenomics
• Humans
• Male
• Prostatic Neoplasms/genetics
• RNA/genetics

• HIF
• Hypoxia
• VEGF
• combination therapy
• dendritic cell

Cisplatin-based chemoradiation (CCRT) offers locally advanced head and neck squamous cell carcinoma (LAHNSCC) patients high local control rate, however, relapses are frequent. Our goal was to evaluate if association of valproic acid (VPA), a histone deacetylase (HDAC) inhibitor, with CCRT improved response rate (RR) and associated biomarkers.

This phase II trial included patients with unresectable locally advanced (LA) oropharynx (OP) squamous cell carcinoma. CCRT began after 2 weeks of VPA (P1). Primary goal was RR at 8 weeks after chemoradiation (CRT)+VPA (P2). Biomarkers included microRNA (miR) polymerase chain reaction (PCR)-array profiling in plasma compared to healthy controls by two-sample t-test. Distribution of p-values was analysed by beta-uniform mixture. Findings were validated by real-time PCR quantitative polymerase chain reaction (qPCR) for selected miRs in plasma and saliva. p16, HDAC2 and RAD23 Homolog B, Nucleotide Excision Repair Protein (HR23B) tumour immunohistochemistry were evaluated.

Given significant toxicities, accrual was interrupted after inclusion of ten LA p16 negative OP patients. All were male, smokers/ex-smokers, aged 41–65 and with previous moderate/high alcohol intake. Nine evaluable patients yielded a RR of 88%. At false discovery rate of 5%, 169 miRs were differentially expressed between patients and controls, including lower expression of tumour suppressors (TSs) such as miR-31, -222, -let-7a/b/e and -145. miR-let-7a/e expression was validated by qPCR using saliva. A HDAC2 H-score above 170 was 90% accurate in predicting 6-month disease-free survival.

VPA and CRT offered high RR; however, with prohibitive toxicities, which led to early trial termination. Patients and controls had a distinct pattern of miR expression, mainly with low levels of TS miRs targeting Tumor protein P53 (TP53). miR-let-7a/e levels were lower in patients compared to controls, which reinforces the aggressive nature of such tumours (NCT01695122).

• chemoradiation
• epigenetics
• head and neck cancer
• microRNA
• valproic acid

• 1-Acylglycerophosphocholine O-Acyltransferase/genetics
• Animals
• Cell Line, Tumor
• Cell Movement/drug effects
• Cell Proliferation/drug effects
• Disease Progression
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Neoplastic/drug effects
• Humans
• Imidazoles/pharmacology
• Indoles/pharmacology
• Male
• Mice
• PC-3 Cells
• Paclitaxel/pharmacology
• Platelet Activating Factor/metabolism
• Prostatic Neoplasms, Castration-Resistant/genetics
• Prostatic Neoplasms, Castration-Resistant/metabolism
• Prostatic Neoplasms, Castration-Resistant/pathology
• Up-Regulation/drug effects

• National Natural Science Foundation of China
• Shanghai Rising-Star Program
• Interdisciplinary research of 9th People's Hospital affiliated to Shanghai Jiao Tong university School of Medicine
• Fundamental research program funding of Ninth People's Hospital affiliated to Shanghai Jiao Tong university School of Medicine

• Calcium
• Cancer
• Chloride
• Immunotherapy
• Inhibitors
• Ion channels
• Potassium
• Sodium

• Cell Membrane/metabolism
• Cell Membrane/pathology
• Cell Proliferation
• Humans
• Ion Channels
• Neoplasms/pathology
• Signal Transduction

• MC_PC_16064 Medical Research Council

• KRAS mutation
• anti-VEGF
• colorectal cancer
• epigenetics
• predictive biomarker

• HDACis as antitumor agents
• Histone deacetylase inhibitors (HDACis)
• QSAR of HDACis
• epigenetic
• histone deacetylases and cancer
• molecular modeling studies of HDACis.
• natural HDACis.

• DNA and histones
• FTIR
• Sodium valproate

• CRPC
• Epigenetics
• HDAC
• PET

• HDAC
• HDAC inhibitors
• HDACi
• cancer
• chromatin
• epigenetics
• epigenomics
• gene networks
• histone deacetylases
• phylogenesis

Sodium valproate/valproic acid (VPA), a histone deacetylase inhibitor, and 5-aza-2-deoxycytidine (5-aza-CdR), a DNA methyltransferase 1 (DNMT1) inhibitor, induce DNA demethylation in several cell types. In HeLa cells, although VPA leads to decreased DNA 5-methylcytosine (5mC) levels, the demethylation pathway involved in this effect is not fully understood. We investigated this process using flow cytometry, ELISA, immunocytochemistry, Western blotting and RT-qPCR in G1 phase-arrested and proliferative HeLa cells compared to the presumably passive demethylation promoted by 5-aza-CdR. The results revealed that VPA acts predominantly on active DNA demethylation because it induced TET2 gene and protein overexpression, decreased 5mC abundance, and increased 5-hydroxy-methylcytosine (5hmC) abundance, in both G1-arrested and proliferative cells. However, because VPA caused decreased DNMT1 gene expression levels, it may also act on the passive demethylation pathway. 5-aza-CdR attenuated DNMT1 gene expression levels but increased TET2 and 5hmC abundance in replicating cells, although it did not affect the gene expression of TETs at any stage of the cell cycle. Therefore, 5-aza-CdR may also function in the active pathway. Because VPA reduces DNA methylation levels in non-replicating HeLa cells, it could be tested as a candidate for the therapeutic reversal of DNA methylation in cells in which cell division is arrested.

The recent discovery of cancer cell plasticity, i.e. their ability to reprogram into cancer stem cells (CSCs) either naturally or under chemotherapy and/or radiotherapy, has changed, once again, the way we consider cancer treatment. If cancer stemness is a reversible epigenetic state rather than a genetic identity, opportunities will arise for therapeutic strategies that remodel epigenetic landscapes of CSCs. However, the systematic use of DNA methyltransferase and histone deacetylase inhibitors, alone or in combination, in advanced solid tumors including colorectal cancers, regardless of their molecular subtypes, does not seem to be the best strategy. In this review, we first summarize the knowledge researchers have gathered on the epigenetic signatures of CSCs with the difficulty of isolating rare populations of cells. We raise questions about the relevant use of currently available epigenetic inhibitors (epidrugs) while the expression of numerous cancer stem cell markers are often repressed by epigenetic mechanisms. These markers include the three cluster of differentiation CD133, CD44 and CD166 that have been extensively used for the isolation of colon CSCs.and . Finally, we describe current treatment strategies using epidrugs, and we hypothesize that, using correlation tools comparing associations of relevant CSC markers with chromatin modifier expression, we could identify better candidates for epienzyme targeting.

• Cancer stem cells
• Colon cancer
• Epigenetics
• Chromatin modifying enzymes
• CD44
• CD133
• CD166

• Clinical trials
• Immunotherapies
• Monoclonal antibodies
• Small molecule inhibitors
• Targeted therapies

• AMPK
• ERG overexpression
• ETS gene fusion
• Metformin
• PTEN
• androgen signaling pathway
• chemotherapy
• histone deacetylase inhibitor
• mTOR
• p53 protein
• prostate cancer
• valproic acid.

• Antipsychotic drugs
• Cancer treatment
• Drug repurposing
• Histone deacetylases
• Phenothiazines

Recurrence with distant metastases has become the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new antineoplastic agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to implement an intensified therapeutic strategy.

The present study examined the combination of the histone deacetylase inhibitor (HDACi) valproic acid (VPA) with fluoropyrimidine-based chemo-radiotherapy on colorectal cancer (CRC) cells.

HCT-116 (p53-wild type), HCT-116 p53^−/− (p53-null), SW620 and HT29 (p53-mutant) CRC cell lines were used to assess the antitumor interaction between VPA and capecitabine metabolite 5′-deoxy-5-fluorouridine (5′-DFUR) in combination with radiotherapy and to evaluate the role of p53 in the combination treatment. Effects on proliferation, clonogenicity and apoptosis were evaluated, along with γH2AX foci formation as an indicator for DNA damage.

Combined treatment with equipotent doses of VPA and 5′-DFUR resulted in synergistic effects in CRC lines expressing p53 (wild-type or mutant). In HCT-116 p53^−/− cells we observed antagonist effects. Radiotherapy further potentiated the antiproliferative, pro-apoptotic and DNA damage effects induced by 5′-DFUR/VPA combination in p53 expressing cells.

These results highlighted the role of VPA as valuable candidate to be added to preoperative chemo-radiotherapy in LARC. On these bases we launched the ongoing phase I/II study of VPA and short-course radiotherapy plus capecitabine as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

The online version of this article (10.1186/s13046-017-0647-5) contains supplementary material, which is available to authorized users.

• Capecitabine
• Colorectal cancer
• HDAC inhibitor
• Radiotherapy
• Valproic acid
• p53

• cancer
• histone deacetylase
• histone deacetylase inhibitors
• target

Androgen receptor (AR) signaling remains the major oncogenic pathway in prostate cancer (PCa). Androgen-deprivation therapy (ADT) is the principle treatment for locally advanced and metastatic disease. However, a significant number of patients acquire treatment resistance leading to castration resistant prostate cancer (CRPC). Epigenetics, the study of heritable and reversible changes in gene expression without alterations in DNA sequences, is a crucial regulatory step in AR signaling. We and others, recently described the technological advance Chem-seq, a method to identify the interaction between a drug and the genome. This has permitted better understanding of the underlying regulatory mechanisms of AR during carcinogenesis and revealed the importance of epigenetic modifiers. In screening for new epigenomic modifiying drugs, we identified SD-70, and found that this demethylase inhibitor is effective in CRPC cells in combination with current therapies. The aim of this review is to explore the role of epigenetic modifications as biomarkers for detection, prognosis, and risk evaluation of PCa. Furthermore, we also provide an update of the recent findings on the epigenetic key processes (DNA methylation, chromatin modifications and alterations in noncoding RNA profiles) involved in AR expression and their possible role as therapeutic targets.

• acetylation
• androgen receptor
• biomarkers
• epigenetics
• methylation
• non-coding RNA
• novel treatments
• prostate cancer

Prostate cancer is one of the most common non-cutaneous malignancies among men worldwide. Epigenetic aberrations, including changes in DNA methylation patterns and/or histone modifications, are key drivers of prostate carcinogenesis. These epigenetic defects might be due to deregulated function and/or expression of the epigenetic machinery, affecting the expression of several important genes. Remarkably, epigenetic modifications are reversible and numerous compounds that target the epigenetic enzymes and regulatory proteins were reported to be effective in cancer growth control. In fact, some of these drugs are already being tested in clinical trials. This review discusses the most important epigenetic alterations in prostate cancer, highlighting the role of epigenetic modulating compounds in pre-clinical and clinical trials as potential therapeutic agents for prostate cancer management.

• DNMTi
• Histone modulators
• Prostate cancer

• Anticonvulsants
• Breast neoplasms
• Colonic neoplasms
• Prostatic neoplasms
• Sodium channels

• Adult
• Aged
• Anti-Arrhythmia Agents/therapeutic use
• Anticonvulsants/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/mortality
• Colorectal Neoplasms/drug therapy
• Colorectal Neoplasms/mortality
• Female
• Humans
• Male
• Middle Aged
• Primary Health Care
• Prostatic Neoplasms/drug therapy
• Prostatic Neoplasms/mortality
• Research Design
• Retrospective Studies
• Sodium Channel Blockers/therapeutic use
• Survival Analysis
• United Kingdom/epidemiology

• Wellcome Trust
• G1000508 Medical Research Council
• 09782 Wellcome Trust

Metastasis is the leading cause of cancer-related deaths. Voltage-gated sodium channels (VGSCs) regulate invasion and metastasis. Several VGSC-inhibiting drugs reduce metastasis in murine cancer models. We aimed to test the hypothesis that patients taking VGSC-inhibiting drugs who developed cancer live longer than those not taking these drugs. A cohort study was performed on primary care data from the QResearch database, including patients with breast, bowel or prostate cancer. Cox proportional hazards regression was used to compare the survival from cancer diagnosis of patients taking VGSC-inhibiting drugs with those not exposed to these drugs. Median time to death was 9.7 years in the exposed group and 18.4 years in the unexposed group, and exposure to these medications significantly increased mortality. Thus, exposure to VGSC-inhibiting drugs associates with reduced survival in breast, bowel and prostate cancer patients. This finding is not consistent with the preclinical data. Despite the strengths of this study including the large sample size, the study is limited by missing information on potentially important confounders such as cancer stage, co-morbidities and cause of death. Further research, which is able to account for these confounding issues, is needed to investigate the relationship between VGSC-inhibiting drugs and cancer survival.

• anticonvulsants
• breast neoplasms
• colonic neoplasms
• prostatic neoplasms
• sodium channels

Solid tumor pathophysiology is characterized by an abnormal microenvironment that guides tumor progression and poses barriers to the efficacy of cancer therapies. Most common among tumor types are abnormalities in the structure of the tumor vasculature and stroma. Remodeling the tumor microenvironment with the aim to normalize any aberrant properties has the potential to improve therapy. In this review, we discuss structural abnormalities of the tumor microenvironment and summarize the therapeutic strategies that have been developed to normalize tumors as well as their potential to enhance therapy. Finally, we present different in vitro models that have been developed to analyze and better understand the effects of the tumor microenvironment on cancer cell behavior.

• in vitro models
• stress alleviation
• tumor vessel permeability
• vascular normalization
• vessel compression

Prostate cancer (PCa) is the most commonly diagnosed solid tumor and the second leading cancer death in the United States, and also one of the major cancer-related deaths in Chinese. Androgen deprivation therapy (ADT) is the first line treatment for metastatic PCa. PCa ultimately relapses with subsequent ADT treatment failure and becomes castrate-resistant (CR). It is important to develop effective therapies with a surrogate marker towards CR PCa.

Histone deacetylase (HDAC) inhibitors were examined to determine their effects in androgen receptor (AR)/cellular prostatic acid phosphatase (cPAcP)-positive PCa cells, including LNCaP C-33, C-81, C4-2 and C4-2B and MDA PCa2b androgen-sensitive and androgen-independent cells, and AR/cPAcP-negative PCa cells, including PC-3 and DU 145 cells. Cell growth was determined by cell number counting. Western blot analyses were carried out to determine AR, cPAcP and PSA protein levels.

cPAcP protein level was increased by HDAC inhibitor treatment. Valproic acid, a HDAC inhibitor, suppressed the growth of AR/cPAcP-positive PCa cells by over 50% in steroid-reduced conditions, higher than on AR/cPAcP-negative PCa cells. Further, HDAC inhibitor pretreatments increased androgen responsiveness as demonstrated by PSA protein level quantitation.

Our results clearly demonstrate that HDAC inhibitors can induce cPAcP protein level, increase androgen responsiveness, and exhibit higher inhibitory activities on AR/cPAcP-positive PCa cells than on AR/cPAcP-negative PCa cells. Upon HDAC inhibitor pretreatment, PSA level was greatly elevated by androgens. This data indicates the potential clinical importance of cPAcP serving as a useful biomarker in the identification of PCa patient sub-population suitable for HDAC inhibitor treatment.

• Biomarker
• Cellular prostatic acid phosphatase
• Histone deacetylase inhibitor
• Prostate cancer

Histone dacetylases (HDACs) are a group of enzymes that remove acetyl groups from histones and regulate expression of tumor suppressor genes. They are implicated in many human diseases, especially cancer, making them a promising therapeutic target for treatment of the latter by developing a wide variety of inhibitors. HDAC inhibitors interfere with HDAC activity and regulate biological events, such as cell cycle, differentiation and apoptosis in cancer cells. As a result, HDAC inhibitor-based therapies have gained much attention for cancer treatment. To date, the FDA has approved three HDAC inhibitors for cutaneous/peripheral T-cell lymphoma and many more HDAC inhibitors are in different stages of clinical development for the treatment of hematological malignancies as well as solid tumors. In the intensifying efforts to discover new, hopefully more therapeutically efficacious HDAC inhibitors, molecular modeling-based rational drug design has played an important role in identifying potential inhibitors that vary in molecular structures and properties. In this review, we summarize four major structural classes of HDAC inhibitors that are in clinical trials and different computer modeling tools available for their structural modifications as a guide to discover additional HDAC inhibitors with greater therapeutic utility.

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Clinical Studies as Topic
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylases/metabolism
• Humans
• Neoplasms/drug therapy
• Neoplasms/metabolism

• G12 MD007595 NIMHD NIH HHS
• U54 GM104940 NIGMS NIH HHS
• 1U54GM104940 NIGMS NIH HHS
• 2G12MD007595 NIMHD NIH HHS

• pfhdac1
• malaria
• valproic acid
• histone deacetylase inhibitor, homology model
• docking
• molecular dynamics
• binding energy

• Antimalarials/chemistry
• Antimalarials/pharmacology
• Catalytic Domain
• Histone Deacetylase 1/antagonists & inhibitors
• Histone Deacetylase 1/chemistry
• Histone Deacetylase Inhibitors/chemistry
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Models, Molecular
• Molecular Docking Simulation
• Plasmodium falciparum/chemistry
• Plasmodium falciparum/drug effects
• Plasmodium falciparum/enzymology
• Protozoan Proteins/antagonists & inhibitors
• Protozoan Proteins/chemistry
• Structural Homology, Protein
• Valproic Acid/chemistry
• Valproic Acid/pharmacology