• Epigenetics
• Head neck carcer
• Histone modification
• MiRNA
• RNA
• incRNa

• Humans
• DNA Methylation
• Epigenesis, Genetic
• Head and Neck Neoplasms/genetics
• Head and Neck Neoplasms/therapy
• Histones/metabolism
• MicroRNAs/genetics

• Biobank
• Dental pulp stem cells
• Dentistry
• Genetics
• Oral cancer
• Oral-systemic disease(s)

Cancer is one of the leading causes of death worldwide. There are only limited treatment strategies that can be applied to treat cancer, including surgical resection, chemotherapy, and radiotherapy, but these have only limited effectiveness. Developing a new drug for cancer therapy is protracted, costly, and inefficient. Recently, drug repurposing has become a rising research field to provide new meaning for an old drug. By searching a drug repurposing database ReDO_DB, a brief list of anesthetic/sedative drugs, such as haloperidol, ketamine, lidocaine, midazolam, propofol, and valproic acid, are shown to possess anti-cancer properties. Therefore, in the current review, we will provide a general overview of the anti-cancer mechanisms of these anesthetic/sedative drugs and explore the potential underlying signaling pathways and clinical application of these drugs applied individually or in combination with other anti-cancer agents.

• anesthetics
• anti-cancer
• anti-proliferation
• apoptosis
• re-purposing
• signaling

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

Breast cancer is the primary problem threatening women’s health. The combined application of valproic acid (VPA) and hydroxyurea (HU) has a synergistic effect on killing breast cancer cells, but the molecular mechanism remains elusive. Replication protein A2 phosphorylation (pRPA2), is essential for homologous recombination (HR) repair and cell cycle. Here we showed that in response to HU, the VPA significantly decreased the tumor cells survival, and promoted S-phase slippage, which was associated with the decrease of pCHK1 and WEE1/pCDK1-mediated checkpoint kinases phosphorylation pathway and inhibited pRPA2/Rad51-mediated HR repair pathway; the mutation of pRPA2 significantly diminished the above effect, indicating that VPA-caused HU sensitization was pRPA2 dependent. It was further found that VPA and HU combination treatment also resulted in the decrease of endonuclease MUS81. After MUS81 elimination, not only the level of pRPA2 was abolished in response to HU treatment, but also VPA-caused HU sensitization was significantly down-regulated through pRPA2-mediated checkpoint kinases phosphorylation and HR repair pathways. In addition, the VPA altered the tumor microenvironment and reduced tumor burden by recruiting macrophages to tumor sites; the Kaplan-Meier analysis showed that patients with high pRPA2 expression had significantly worse survival. Overall, our findings demonstrated that VPA influences HR repair and cell cycle through down-regulating MUS81-pRPA2 pathway in response to HU treatment.

• HR
• HU
• MUS81
• VPA
• breast cancer
• cell cycle
• pRPA2

• cancer
• chemical biology
• molecular biology
• oncology

• Acetylation/drug effects
• DNA Methylation/drug effects
• Double-Blind Method
• Female
• Head and Neck Neoplasms/drug therapy
• Head and Neck Neoplasms/metabolism
• Histones/metabolism
• Humans
• Male
• Prospective Studies
• Squamous Cell Carcinoma of Head and Neck/drug therapy
• Squamous Cell Carcinoma of Head and Neck/metabolism
• Valproic Acid/therapeutic use

• 001 World Health Organization

Sodium valproate (VPA) has been associated with a reduced risk of head and neck cancer development. The potential protective mechanism of action is believed to be via inhibition of histone deacetylase and subsequent epigenetic reprogramming. SAVER is a phase IIb open-label, randomised control trial of VPA as a chemopreventive agent in patients with high-risk oral epithelial dysplasia (OED). The aim of the trial is to gather preliminary evidence of the clinical and biological effects of VPA upon OED and assess the feasibility and acceptability of such a trial, with a view to inform a future definitive phase III study.

One hundred and ten patients with high-risk OED will be recruited from up to 10 secondary care sites in the UK and randomised into either VPA or observation only for 4 months. Women of childbearing potential will be excluded due to the teratogenic properties of VPA. Tissue and blood samples will be collected prior to randomisation and on the last day of the intervention/observation-only period (end of 4 months). Clinical measurement and additional safety bloods will be taken at multiple time points during the trial. The primary outcome will be a composite, surrogate endpoint of change in lesion size, change in grade of dysplasia and change in LOH profile at 8 key microsatellite regions. Feasibility outcomes will include recruitment targets, compliance with the study protocol and adverse effects. A qualitative sub-study will explore patient experience and perception of the trial.

The current management options for patients with high-risk OED are limited and mostly include surgical resection and clinical surveillance. However, there remains little evidence whether surgery can effectively lead to a notable reduction in the risk of oral cancer development. Similarly, surveillance is associated with concerns regarding delayed diagnosis of OED progressing to malignancy. The SAVER trial provides an opportunity to investigate the effects of a repurposed, inexpensive and well-tolerated medication as a potential chemopreventive strategy for patients with high-risk OED. The clinical and biological findings of SAVER will inform the appropriateness, design and feasibility of a definitive phase III trial.

The trial is registered with the European Clinical Trials Database (Eudra-CT 2018-000197-30). (http://www.isrctn.com/ISRCTN12448611). The trial was prospectively registered on 24/04/2018.

The online version contains supplementary material available at 10.1186/s13063-021-05373-8.

• Chemoprevention
• Drug repurposing
• Epigenetic reprogramming
• Oral epithelial dysplasia
• Randomised controlled trial
• Sodium valproate

• bladder cancer
• epigenetic deregulation
• retinoic acid

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

• drug
• repositioning
• repurposing
• oncology

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

Programmed cell death 4 (PDCD4) as a tumor suppressor gene inhibits growth and metastasis of cancer cells, which involved with eIF4A1, the inhibitor of translation initiation. Although the prognosis of early-stage oral squamous cell carcinoma (OSCC) is generally better, but many patients occur recurrence after surgery. Understanding the clinical expression pattern of PDCD4/eIF4A1 signal would provide diagnostic biomarker and target therapy premise for early-stage OSCC patients.

Immunohistochemical analysis was performed on 69 early-stage (T1/2N0M0) OSCC samples to evaluate temporal expression and prognostic value of eIF4A1 and PDCD4 in early-stage OSCC according to cell types and microlocalization. The correlations between PDCD4/eIF4A1 signal and Ki-67, postoperative recurrence and metastasis were determined.

We found that PDCD4 was presented in tumor cells (TCs) and tumor-infiltrating lymphocytes (TILs) but absent in fibroblast-like cells (FLCs). eIF4A1 was only presented in TCs. PDCD4^TCs was negative associated with eIF4A1^TCs in tumor center, and patients with low PDCD4^TCs or high eIF4A1^TCs had poorer differentiation. Moreover, aberrant PDCD4/eIF4A1 signal led to higher Ki-67 level. Interestingly, patients with low expressed PDCD4^TILs had better prognosis, indicating the function heterogeneity of PDCD4 in different cell types. Furthermore, low PDCD4 ^TCs and high eIF4A1^TCs predicted higher postoperative recurrence rate and are significant independent risk factors for early-stage OSCC.

Patients with low PDCD4^TCs and high eIF4A1^TCs have higher recurrence rate and poor clinical outcome. Of note, PDCD4^TILs exerts contradictory function. Thus, PDCD4/eIF4A1 targeting therapeutics should consider the function heterogeneity of PDCD4.

• PDCD4
• diagnosis
• eIF4A1
• early-stage OSCC
• prognosis

• CCND1
• CDK4
• IFITM3
• Oral squamous cell carcinoma
• Proliferation

• Adult
• Aged
• Aged, 80 and over
• Apoptosis
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Cycle Checkpoints
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cellular Senescence
• Cyclin D1/metabolism
• Cyclin-Dependent Kinase 4/metabolism
• Female
• Gene Knockdown Techniques
• Humans
• Male
• Membrane Proteins/metabolism
• Middle Aged
• Mouth Mucosa/pathology
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology
• Phosphorylation
• RNA-Binding Proteins/metabolism
• Retinoblastoma Protein/metabolism
• Signal Transduction

• P30 CA076292 NCI NIH HHS
• 06-00-00-0000 Kementerian Sains, Teknologi dan Inovasi
• UM.C/625/1/HIR/MOHE/DENT-03 Universiti Malaya
• not applicable Cancer Research Malaysia

• 4SC-202
• apoptosis
• metformin
• oral squamous cell carcinoma
• ΔNp63

• Animals
• Apoptosis/drug effects
• Benzamides/pharmacology
• Carcinoma, Squamous Cell/genetics
• Carcinoma, Squamous Cell/metabolism
• Carcinoma, Squamous Cell/pathology
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cell Transformation, Neoplastic/genetics
• Cell Transformation, Neoplastic/metabolism
• Female
• Humans
• Metformin/pharmacology
• Mice
• Mouth Neoplasms/genetics
• Mouth Neoplasms/metabolism
• Mouth Neoplasms/pathology
• Signal Transduction/drug effects
• Transcription Factors/genetics
• Transcription Factors/metabolism
• Tumor Suppressor Proteins/genetics
• Tumor Suppressor Proteins/metabolism
• Ubiquitination

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

• betel quid
• oral cancer
• sirtuin
• transforming growth factor beta

• Leukoplakia
• Malignant transformation
• Management
• Oral potentially malignant disorders
• Risk assessment
• Screening

Head and neck squamous carcinoma (HNSCC) is the sixth most prevalent cancer and one of the most aggressive malignancies worldwide. Despite continuous efforts to identify molecular markers for early detection, and to develop efficient treatments, the overall survival and prognosis of HNSCC patients remain poor. Accumulated scientific evidences suggest that epigenetic alterations, including DNA methylation, histone covalent modifications, chromatin remodeling and non-coding RNAs, are frequently involved in oral carcinogenesis, tumor progression, and resistance to therapy. Epigenetic alterations occur in an unsystematic manner or as part of the aberrant transcriptional machinery, which promotes selective advantage to the tumor cells. Epigenetic modifications also contribute to cellular plasticity during tumor progression and to the formation of cancer stem cells (CSCs), a small subset of tumor cells with self-renewal ability. CSCs are involved in the development of intrinsic or acquired therapy resistance, and tumor recurrences or relapse. Therefore, the understanding and characterization of epigenetic modifications associated with head and neck carcinogenesis, and the prospective identification of epigenetic markers associated with CSCs, hold the promise for novel therapeutic strategies to fight tumors. In this review, we focus on the current knowledge on epigenetic modifications observed in HNSCC and emerging Epi-drugs capable of sensitizing HNSCC to therapy.

• DNA methylation
• HNSCC (Head and Neck Squamous Cell Carcinoma)
• acetylation
• cancer stem cell
• chemoresistance
• epigenetics
• histone H3
• histone modifications
• microRNA

Radiotherapy is an effective treatment for the majority of types of localized solid cancer. However, the risk of side effects to the surrounding normal tissues limits radiotherapeutic approaches. Whilst the mechanism of action of valproic acid, an inhibitor of histone deacetylase, remains unknown, the inhibitor is a potential antineoplastic radiosensitizer. The present study demonstrated the in vitro radiosensitizing effects of valproic acid on the human breast cancer MCF7 cell line, and revealed that valproic acid increased the level of DNA breakage, apoptosis and senescence. In addition, western blot analyses revealed that valproic acid induced tumor suppressor protein (p)53 and p21 expression, and activated checkpoint kinase 2 (CHK2) in MCF7 cells and primary mouse embryonic fibroblasts. Notably, treatment with valproic acid also induced increases in the level of p21 protein levels and CHK2 activity in p53-null colon cancer HCT116 cells. Furthermore, the present study demonstrated that valproic acid-induced radiosensitization was largely dependent on the activity of CHK2. The results of the present study reveal that valproic acid may exhibit clinical utility with respect to increasing the anticancer efficacy of radiotherapy by affecting the level of p53.

• checkpoint kinase 2
• p21
• radiosensitizer
• senescence
• valproic acid

• Hair loss
• High-grade glioma
• Radiotherapy
• Valproic acid

Programmed cell death protein 4 (PDCD4) is a novel tumor suppressor protein involved in programmed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical significance and prognostic value of PDCD4 in solid tumors.

A systematic literature review was performed to retrieve publications with available clinical information and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta-analysis Of Observational Studies in Epidemiology group. Pooled odds ratios (ORs), hazard ratios (HRs), and 95% confidence intervals (CIs) for survival analysis were calculated. Publication bias was examined by Begg’s and Egger’s tests.

Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was significantly associated with the differentiation status of head and neck cancer (OR 4.25, 95% CI 1.87–9.66) and digestive system cancer (OR 2.87, 95% CI 1.84–4.48). Down-regulation of PDCD4 was significantly associated with short overall survival of patients with head and neck (HR: 3.44, 95% CI 2.38–4.98), breast (HR: 1.86, 95% CI 1.36–2.54), digestive system (HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers (HR: 3.16, 95% CI 1.06–9.41).

The current evidence suggests that PDCD4 down-regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be confirmed by large-scale prospective studies.

• Disease-free survival
• Meta-analysis
• Overall survival
• Prognosis
• Programmed cell death protein 4 (PDCD4)
• Recurrence-free survival
• Solid tumor

Aberrant histone deacetylase (HDAC) has a key role in the neoplastic process associated with the epigenetic patterns of tumor-related genes. The present study was performed to investigate the effects and determine the mechanism of action of the HDAC inhibitor, valproic acid (VPA), on the CAL27 cell line derived from oral squamous cell carcinoma (OSCC). The effects of VPA on the viability of CAL27 cells were investigated using MTT assays. Alterations in the cell cycle and apoptosis were also examined using propidium iodide (PI) and Annexin V-PI assays, and were subequently analyzed by flow cytometry. Small ubiquitin-related modifier (SUMO)-related genes were evaluated by reverse transcription-quantitative polymerase chain reaction analysis. In addition, the effects of VPA were assessed using a xenograft model in vivo. The present results demonstrated significant dose-dependent inhibition of cell viability following VPA treatment. Treatment with VPA increased the distribution of CAL27 cells in the G₁ phase and reduced cells in the S phase, and significantly increased the expression levels of SUMO1 and SUMO2 (P<0.01). Using a xenograft model, the mean tumor volume in VPA-treated animals was demonstrated to be significantly reduced, and the rate of apoptosis was significantly increased, as compared with the control animals. These results suggested that VPA may regulate SUMOylation, producing an anticancer effect in vivo. Further investigation into the role of VPA in tumorigenesis may identify novel therapeutic targets for OSCC.

• CAL27 cells
• histone deacetylase
• oral squamous cell carcinoma
• small ubiquitin-related modifier
• valproic acid

• Oct4
• meningioma
• radiosensitization
• tumor stem-like cells
• valproic acid

Histone deacetylase inhibitors (HDIs) are promising anticancer drugs, which inhibit proliferation of a wide variety of cancer cells including breast carcinoma cells. In the present study, we investigated the influence of valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), alone or in combination with cisplatin (CDDP) on proliferation, induction of apoptosis and cell cycle progression in MCF7, T47D and MDA-MB-231 human breast carcinoma cell lines. The type of interaction between HDIs and CDDP was determined by an isobolographic analysis. The isobolographic analysis is a very precise and rigorous pharmacodynamic method, to determine the presence of synergism, addition or antagonism between different drugs with using variety of fixed dose ratios. Our experiments show that the combinations of CDDP with SAHA or VPA at a fixed-ratio of 1:1 exerted additive interaction in the viability of MCF7 cells, while in T47D cells there was a tendency to synergy. In contrast, sub-additive (antagonistic) interaction was observed for the combination of CDDP with VPA in MDA-MB-231 “triple-negative” (i.e. estrogen receptor negative, progesterone receptor negative, and HER-2 negative) human breast cancer cells, whereas combination of CDDP with SAHA in the same MDA-MB-231 cell line yielded additive interaction. Additionally, combined HDIs/CDDP treatment resulted in increase in apoptosis and cell cycle arrest in all tested breast cancer cell lines in comparison with a single therapy. In conclusion, the additive interaction of CDDP with SAHA or VPA suggests that HDIs could be combined with CDDP in order to optimize treatment regimen in some human breast cancers.

• Antineoplastic Agents/pharmacology
• Apoptosis/drug effects
• Cell Cycle Checkpoints/drug effects
• Cell Line, Tumor
• Cell Proliferation/drug effects
• Cisplatin/pharmacology
• Dose-Response Relationship, Drug
• Drug Synergism
• Drug Therapy, Combination
• Female
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Hydroxamic Acids/pharmacology
• Inhibitory Concentration 50
• MCF-7 Cells
• Valproic Acid/pharmacology
• Vorinostat

• anticancer therapy
• histone deacetylase inhibitors
• histone deacetylases
• oral squamous cell carcinoma

Valproic acid (VPA) has been identified as a histone deacetylase inhibitor, inducing differentiation in transformed cells. However, no study has shown the effect of VPA in the redifferentiation induction and stemness of anaplastic thyroid. The main objective of this study was to evaluate the efficacy of VPA as a differentiation therapy agent in human thyroid cancer based on its effect on stemness and differentiation process. Indications for differentiation of 8305C and B-CPAP cell lines following VPA treatment were obtained by analyzing cell proliferation rate, morphological changes, adherent-dependent colony formation, and Hoechst 33342 staining. The expressions of stemness, differentiation, and aggressiveness specific marker genes were measured by quantitative RT-PCR. VPA treatment effectively showed growth inhibition in both cell lines. The high nuclear-cytoplasmic (N : C) ratio of 8305C cells markedly decreased and treated cells became more epithelial-like. Treated cells showed stronger Hoechst 33342 fluorescence compared with control cells. The hTERT and OCT-4 reduction was paralleled with adherent-dependent colony formation decrement in both cell lines. VPA effectively induced NIS and TTF-1 in anaplastic cells, it whereas showed no clear pattern in papillary cell line. VPA treatment also resulted in the reduction of MMP-2 and MMP-9. These finding suggest that VPA could redifferentiate the anaplastic thyroid cancer cells.

Hepatocarcinogenesis is associated with epigenetic changes, including histone deacetylases (HDACs). Epigenetic modulation by HDAC inhibition is a potentially valuable approach for hepatocellular carcinoma treatment. In present study, we evaluated the anticancer effects of sodium valproate (SVP), a known HDAC inhibitor, in human hepatocarcinoma cells. The results showed SVP inhibited the proliferation of Bel-7402 cells in a dose-dependent manner. Low dose SVP treatment caused a large and flat morphology change, positive SA-β-gal staining, and G0/G1 phase cell cycle arrest in human hepatocarcinoma cells. Low dose SVP treatment also increased acetylation of histone H3 and H4 on p21 promoter, accompanied by up-regulation of p21 and down-regulation of RB phosphorylation. These observations suggested that a low dose of SVP could induce cell senescence in hepatocarcinoma cells, which might correlate with hyperacetylation of histone H3 and H4, up-regulation of p21, and inhibition of RB phosphorylation. Since the effective concentration inducing cell senescence in hepatocarcinoma cells is clinically available, whether a clinical dose of SVP could induce cell senescence in clinical hepatocarcinoma is worthy of further study.

Head and neck squamous cell carcinoma is the sixth most common cancer in the world with approximately 650000 new cases diagnosed annually. Next-generation molecular techniques and results from phase 2 of the Cancer Genome Atlas becoming available have drastically improved our current knowledge on the genetics basis of head and neck squamous cell carcinoma. New insights and new perspectives on the mutational landscape implicated in head and neck squamous cell carcinoma provide improved tools for prognostication. More importantly, depend on the patient’s tumor subtypes and prognosis, deescalated or more aggressive therapy maybe chosen to achieve greater potency while minimizing the toxicity of therapy. This paper aims to review our current knowledge on the genetic mutations and altered molecular pathways in head and neck squamous cell carcinoma. Some of the most common mutations in head and neck squamous cell carcinoma reported by the cancer genome atlas including TP53, NOTCH1, Rb, CDKN2A, Ras, PIK3CA and EGFR are described here. Additionally, the emerging role of epigenetics and the role of human papilloma virus in head and neck squamous cell carcinoma are also discussed in this review. The molecular pathways, clinical applications, actionable molecular targets and potential therapeutic strategies are highlighted and discussed in details.

• Head and neck squamous cell carcinoma
• TP53
• Ras/PIK3CA
• NOTCH1/p63
• HPV/E6/E7/Rb/CDKN2A

• Acetylation
• Chromatin compaction
• Genetic code
• H3
• H4
• Histone modifications
• Oral cancer
• Whole genome sequencing