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

• Anticancer drugs
• Cancer therapeutics
• Drug discovery
• Drug repurposing
• Multitargeting
• Non-cancer drugs

• cancer
• diet
• microbes
• misconceptions
• nutrition
• prevention
• risk factors

• RES0047455 CIHR

• anticancer activities
• histone deacetylase inhibitors
• pre-clinical and clinical studies
• short-chain fatty acids
• valproic acid

As a malignant tumor of the central nervous system, glioma exhibits high incidence and poor prognosis. Circular RNA HIPK3 (circHIPK3) is a circular RNA (circRNA) related to cancer progression. However, the role of circHIPK3 in gliomas remains unclear. The purpose of this study was to investigate the role of circHIPK3 in gliomas and its mechanism. The qRT-PCR method was used to determine the expression pattern of circHIPK3 in glioma cell lines. CCK-8 assay was used to detect cell proliferation. Cell migration and invasion were evaluated using the Transwell assay. Our results showed that circHIPK3 expression was significantly up-regulated in glioma tissues and cell lines. In vitro, the down-regulation of circHIPK3 significantly inhibited the proliferation, migration and invasion of glioma cells. Besides, we demonstrated that circHIPK3 acted as a sponge to absorb miR-124 and promoted CCND2 expression. In summary, our results indicated that circHIPK3 had carcinogenic effects by regulating the expression of CCND2 in glioma by sponging miR-124. These findings provided favorable evidence to reveal the role of circHIPK3 in the development of gliomas.

• circHIPK3
• circular RNA
• glioma
• invasion
• miR-124
• proliferation

The mammalian protein kinase C-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3) is a multi-domain monothiol glutaredoxin that is involved in a wide variety of signaling pathways and biological processes. PICOT is required for normal and transformed cell growth and is critical for embryonic development. Recent studies in T lymphocytes demonstrated that PICOT can translocate to the nucleus and interact with embryonic ectoderm development, a polycomb group protein and a core component of the polycomb repressive complex 2, which contributes to the maintenance of transcriptional repression and chromatin remodeling. Furthermore, PICOT was found to interact with chromatin-bound embryonic ectoderm development and alter the extent of histone 3 lysine 27 trimethylation at the promoter region of selected polycomb repressive complex 2 target genes. PICOT knockdown in Jurkat T cells led to increased histone 3 lysine 27 trimethylation at the promoter region of CCND2, a cell cycle-regulating gene which encodes the cyclin D2 protein. As a result, the expression levels of CCND2 mRNA and protein levels were reduced, concomitantly with inhibition of the cell growth rate. Analysis of multiple data sets from the Cancer Genome Atlas revealed that a high expression of PICOT correlated with a low expression of CCND2 in a large number of human cancers. In addition, this parameter correlated with poor patient survival, suggesting that the ratio between PICOT/CCND2 mRNA levels might serve as a predictor of patient survival in selected types of human cancer.

• Protein kinase C-interacting cousin of thioredoxin
• Glutaredoxin 3
• Cyclin D2
• Histone methylation
• T lymphocyte
• Histone 3 lysine 27 trimethylation

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

• drug
• repositioning
• repurposing
• oncology

• Antineoplastic Agents/therapeutic use
• Clinical Trials as Topic
• Drug Repositioning
• Humans
• Neoplasms/drug therapy

Neuroendocrine differentiation of prostate cancer, induced by androgen deprivation therapy, is mainly related to advanced disease and poor clinical outcome. Genetic and epigenetic alterations are the key elements of the prostate carcinogenesis. A group of compounds able to induce changes in this sense is inhibitors of histone deacetylase, to which it belongs valproic acid (VPA). In the present paper, we evaluated the role of this molecule on the neuroendocrine differentiation of LNCaP cells together with the effect on proliferation and survival signals.

Cell growth was analyzed by MTT and flow cytometry, while expression of proteins through Western blot analysis.

Our results have documented that VPA in LNCaP cells reduces cell proliferation, decreases the S phase and Cyclin A, and up-regulates the cyclin-dependent kinase inhibitors p21waf and p27. The acquisition of androgen-independent condition is consistent with an induction of β-III Tubulin and gamma Enolase, both markers of neuroendocrine phenotype. However, all these features cease with the removal of valproate from the culture medium, demonstrating the transitory nature of the epigenetic event. The VPA treatment does not compromise the survival phosphorylated signals of Akt, ERK1/2 and mTOR/p70S6K that remain up-regulated. Consistently, there is an increase of phospho-FOXO3a, to which corresponds the decreased expression of the corresponding oncosuppressor protein.

Overall, our findings indicate that VPA in LNCaP prostate tumor cells, although it reduces cell proliferation, is able to drive neuroendocrine phenotype and to maintain the survival of these cells. Keeping in mind that neuroendocrine differentiation of prostate cancer appears to be associated with a poor prognosis, it is necessary to develop new treatments that do not induce neurodifferentiation but able to counteract cell survival.

• cell cycle
• cell proliferation
• neuroendocrine tumor
• prostate cancer

Protein kinase C (PKC)-interacting cousin of thioredoxin (PICOT; also termed glutaredoxin 3 (Grx3; Glrx3)) is a ubiquitous protein that can interact with the embryonic ectoderm development (EED) protein via each of its two C-terminal PICOT/Grx homology domains. Since EED is a Polycomb-Group protein and a core component of the polycomb repressive complex 2 (PRC2), we tested the involvement of PICOT in the regulation of PRC2-mediated H3 lysine 27 trimethylation (H3K27me3), transcription and translation of selected PRC2 target genes. A fraction of the cellular PICOT protein was found in the nuclei of leukemia cell lines, where it was associated with the chromatin. In addition, PICOT coimmunoprecipitated with chromatin-residing EED derived from Jurkat and COS-7 cell nuclei. PICOT knockdown led to a reduced H3K27me3 mark and a decrease in EED and EZH2 at the CCND2 gene promoter. In agreement, PICOT-deficient T cells exhibited a significant increase in CCND2 mRNA and protein expression. Since elevated expression levels of PICOT were reported in several different tumors and correlated in the current studies with decreased transcription and translation of the CCND2 gene, we tested whether this opposite correlation exists in human cancers. Data from the Cancer Genome Atlas (TCGA) database indicated statistically significant negative correlation between PICOT and CCND2 in eight different human tumors where the highest correlation was in lung (p = 8.67E−10) and pancreatic (p = 1.06E−5) adenocarcinoma. Furthermore, high expression of PICOT and low expression of CCND2 correlated with poor patient survival in five different types of human tumors. The results suggest that PICOT binding to chromatin-associated EED modulates the H3K27me3 level at the CCND2 gene promoter which may be one of the potential mechanisms for regulation of cyclin D2 expression in tumors. These findings also indicate that a low PICOT/CCND2 expression ratio might serve as a good predictor of patient survival in selected human cancers.

Nitroglycerin (NG), a nitric oxide donor, and valproic acid (VPA), an inhibitor of histone deacetylases, have impressive effects on numerous cancer cell lines. This study intended to evaluate synergistic effects of NG and VPA on cell viability and apoptosis in K562 cells. K562 cells were cultured in RPMI-1640 supplemented with 10 % heat-inactivated FBS. They were treated with different doses of NG, VPA and cisplatin for 24, 48, and 72 h, and MTT assay was performed to analyze cell viability. Also, Peripheral blood mononuclear cells (PBMC) were cultured in RPMI-1640 media and incubated with NG (200 μM), VAP (100 μM), NG+VPA (150 μM) and cisplatin (8 μM) to evaluate cytotoxicity. IC₅₀ of the drugs, when they were applied separately and in combination, were calculated using the COMPUSYN software. DNA electrophoresis, TUNEL assay, and Hoechst staining were performed to investigate apoptosis induction. RT-PCR was used for the evaluation of apoptotic genes expression. The results of the MTT assay showed that cell viability decreased at all applied doses of NG and VPA. It was noticed that the cytotoxic effects of these drugs were dose- and time-dependent. Based on the COMPUSYN output, the combination of the drugs (VPA and NG) in a certain ratio concentration synergistically decreased cell viability. Cisplatin significantly decreased cell viability of PBMCs and K562 cells. Also, the combination drug had cytotoxic effect and significantly reduced viability of K562 cells compared with PBMCs and control cells. In the target cells treated with this combination, Bax and caspase-3 expression increased but Bcl-2 expression decreased. These results suggest that NG, VPA, and their combination decreased cell viability and induced apoptosis via the intrinsic apoptotic pathway. This study suggests that this combination therapy can be considered for further evaluation as an effective chemotherapeutic strategy for patients with chronic myeloid leukemia.

• K562 cells
• apoptosis
• combination therapy
• cytotoxicity
• nitroglycerine
• valproic acid

Drug repurposing is the idea of using an already approved drug for another disease or disorder away from its initial use. This new approach ensures the reduction in high cost required for developing a new drug in addition to the time consumed, especially in the tumor disorders that show an unceasing rising rate with an unmet success rate of new anticancer drugs. In our review, we will review the anti-cancer effect of some CNS drugs, including both therapeutic and preventive, by searching the literature for preclinical or clinical evidence for anticancer potential of central nervous system drugs over the last 8 years period (2010-2018) and including only evidence from Q1 journals as indicated by Scimago website (www.scimagojr.com). We concluded that Some Central Nervous system drugs show a great potential as anti-cancer in vitro, in vivo and clinical trials through different mechanisms and pathways in different types of cancer that reveal a promising evidence for the repurposing of CNS drugs for new indications.

• CNS drug
• cancer
• repositioning
• repurposable drugs

• Animals
• Antineoplastic Agents/administration & dosage
• Blood-Brain Barrier/metabolism
• Brain Neoplasms/drug therapy
• Brain Neoplasms/genetics
• Brain Neoplasms/metabolism
• Drug Delivery Systems
• Drug Discovery
• Glioblastoma/drug therapy
• Glioblastoma/genetics
• Glioblastoma/metabolism
• Humans
• Proteomics

• R01 CA193690 NCI NIH HHS

The RTK/ERK signaling pathway has been implicated in prostate cancer progression. However, the genetic relevance of this pathway to aggressive prostate cancer at the SNP level remains undefined. Here we performed a SNP and gene-based association analysis of the RTK/ERK pathway with aggressive prostate cancer in a cohort comprising 956 aggressive and 347 non-aggressive cases. We identified several loci including rs3217869/CCND2 within the pathway shown to be significantly associated with aggressive prostate cancer. Our functional analysis revealed a statistically significant relationship between rs3217869 risk genotype and decreased CCND2 expression levels in a collection of 119 prostate cancer patient samples. Reduced expression of CCND2 promoted cell proliferation and its overexpression inhibited cell growth of prostate cancer. Strikingly, CCND2 downregulation was consistently observed in the advanced prostate cancer in 18 available clinical data sets with a total amount of 1,095 prostate samples. Furthermore, the lower expression levels of CCND2 markedly correlated with prostate tumor progression to high Gleason score and elevated PSA levels, and served as an independent predictor of biochemical relapse and overall survival in a large cohort of prostate cancer patients. Together, we have identified an association of genetic variants and genes in the RTK/ERK pathway with prostate cancer aggressiveness, and highlighted the potential importance of CCND2 in prostate cancer susceptibility and tumor progression to metastasis.

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

• Breast cancer cells
• Cell cycle
• Cell death
• Cyclin D2
• ERK1/2 activation
• Pep5

Prostate cancer (PCa) is one of the most incident cancers worldwide but clinical and pathological parameters have limited ability to discriminate between clinically significant and indolent PCa. Altered expression of histone methyltransferases and histone methylation patterns are involved in prostate carcinogenesis. SMYD3 transcript levels have prognostic value and discriminate among PCa with different clinical aggressiveness, so we decided to investigate its putative oncogenic role on PCa.

We silenced SMYD3 and assess its impact through in vitro (cell viability, cell cycle, apoptosis, migration, invasion assays) and in vivo (tumor formation, angiogenesis). We evaluated SET domain's impact in PCa cells' phenotype. Histone marks deposition on SMYD3 putative target genes was assessed by ChIP analysis.

Knockdown of SMYD3 attenuated malignant phenotype of LNCaP and PC3 cell lines. Deletions affecting the SET domain showed phenotypic impact similar to SMYD3 silencing, suggesting that tumorigenic effect is mediated through its histone methyltransferase activity. Moreover, CCND2 was identified as a putative target gene for SMYD3 transcriptional regulation, through trimethylation of H4K20.

Our results support a proto-oncogenic role for SMYD3 in prostate carcinogenesis, mainly due to its methyltransferase enzymatic activity. Thus, SMYD3 overexpression is a potential biomarker for clinically aggressive disease and an attractive therapeutic target in PCa.

• SET domain
• SMYD3
• cyclin D2
• histone methyltransferase
• prostate cancer

• Antiepileptic drugs
• Case–control
• Histone deacetylase inhibitors
• Prostatic neoplasms

Valproic acid (VPA) is a clinically available histone deacetylase inhibitor with promising anticancer attributes. Recent studies have demonstrated the anticancer effects of VPA on prostate cancer cells. However, little is known about the differential effects of VPA between metastatic and non-metastatic prostate cancer cells and the relationship between the expression of metastasis suppressor proteins and VPA. In the present study, we demonstrate that inhibition of cell viability and invasion by VPA was more effective in the metastatic prostate cancer cell line PC3 than in the tumorigenic but non-metastatic prostate cell line, RWPE2. Further, we identified that the metastasis suppressor NDRG1 is upregulated in PC3 by VPA treatment. In contrast, NDRG1 was not increased in RWPE2 cells. Also, the suppressed invasion of PC3 cells by VPA treatment was relieved by NDRG1 knockdown. Taken together, we suggest that the anticancer effect of VPA on prostate cancer cells is, in part, mediated through upregulation of NDRG1. We also conclude that VPA has differential effects on the metastasis suppressor gene and invasion ability between non-metastatic and metastatic prostate cancer cells.

• Cell cycle
• Pluripotency
• Senescence
• Stem cell
• Valproic acid
• iPSC
• p16
• p21

• CDK4
• cyclin D1
• oncogenes
• radiation therapy
• targeted chemotherapy
• tumor-suppressor gene s

Although p300 and CBP lysine acetyltransferases are often treated interchangeably, the inability of one enzyme to compensate for the loss of the other suggests unique roles for each. As these deficiencies coincide with aberrant levels of histone acetylation, we hypothesized that the key difference between p300 and CBP activity is differences in their specificity/selectivity for lysines within the histones. Utilizing a label-free, quantitative mass spectrometry based technique, we determined the kinetic parameters of both CBP and p300 at each lysine of H3 and H4, under conditions we would expect to encounter in the cell (either limiting acetyl-CoA or histone). Our results show that while p300 and CBP acetylate many common residues on H3 and H4, they do in fact possess very different specificities, and these specificities are dependent on whether histone or acetyl-CoA is limiting. Steady-state experiments with limiting H3 demonstrate that both CBP and p300 acetylate H3K14, H3K18, H3K23, with p300 having specificities up to 10¹⁰-fold higher than CBP. Utilizing tetramer as a substrate, both enzymes also acetylate H4K5, H4K8, H4K12, and H4K16. With limiting tetramer, CBP displays higher specificities, especially at H3K18, where CBP specificity is 10³²-fold higher than p300. With limiting acetyl-CoA, p300 has the highest specificity at H4K16, where specificity is 10¹⁸-fold higher than CBP. This discovery of unique specificity for targets of CBP- vs p300-mediated acetylation of histone lysine residues presents a new model for understanding their respective biological roles and possibly an opportunity for selective therapeutic intervention.