scholarly journals Histone Deacetylase Inhibitors in the Treatment of Hepatocellular Carcinoma: Current Evidence and Future Opportunities

2021 ◽  
Vol 11 (3) ◽  
pp. 223
Author(s):  
Nikolaos Garmpis ◽  
Christos Damaskos ◽  
Anna Garmpi ◽  
Vasiliki E. Georgakopoulou ◽  
Panagiotis Sarantis ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitor ◽  
Treatment Strategies ◽  
Current Evidence ◽  
Therapeutic Effects ◽  
Major Health Problem ◽  
Sorafenib Treatment

Hepatocellular carcinoma (HCC) remains a major health problem worldwide with a continuous increasing prevalence. Despite the introduction of targeted therapies like the multi-kinase inhibitor sorafenib, treatment outcomes are not encouraging. The prognosis of advanced HCC is still dismal, underlying the need for novel effective treatments. Apart from the various risk factors that predispose to the development of HCC, epigenetic factors also play a functional role in tumor genesis. Histone deacetylases (HDACs) are enzymes that remove acetyl groups from histone lysine residues of proteins, such as the core nucleosome histones, in this way not permitting DNA to loosen from the histone octamer and consequently preventing its transcription. Considering that HDAC activity is reported to be up-regulated in HCC, treatment strategies with HDAC inhibitors (HDACIs) showed some promising results. This review focuses on the use of HDACIs as novel anticancer agents and explains the mechanisms of their therapeutic effects in HCC.

scholarly journals Current locoregional therapies and treatment strategies in hepatocellular carcinoma

2020 ◽  
Vol 27 (S3) ◽  
Author(s):  
L. Cardarelli-Leite ◽  
A. Hadjivassiliou ◽  
D. Klass ◽  
J. Chung ◽  
S.G.F. Ho ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Current Evidence ◽  
Percutaneous Ablation ◽  
Transarterial Radioembolization ◽  
Combined Use ◽  
Liver Morphology ◽  
Locoregional Therapies ◽  
Bridging To Transplant

Locoregional therapies (LRT) play an important role in the treatment of hepatocellular carcinoma (HCC), with the aim of increasing overall survival while preserving liver function. Different forms of LRT are available and choosing which one is best will depend on technical aspects, liver morphology, tumor biology, and patient’s symptoms. The purpose of this review article is to provide an overview of the current evidence regarding the use of percutaneous ablation, transarterial chemoembolization and transarterial radioembolization for the curative or palliative treatment of HCC. Special situations are also reviewed, including the combined use of systemic therapy with LRT; indications and techniques for bridging to transplant and downstaging; and the use of LRT to treat patients with HCC and macrovascular invasion.

scholarly journals The Synergistic Anti-Cancer Effects of NVP-BEZ235 and Regorafenib in Hepatocellular Carcinoma

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2454
Author(s):  
Cheng-Chan Yu ◽  
Sung-Ying Huang ◽  
Shu-Fang Chang ◽  
Kuan-Fu Liao ◽  
Sheng-Chun Chiu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Western Blot ◽  
Kinase Inhibitor ◽  
Epithelial Mesenchymal Transition ◽  
Combined Treatment ◽  
Gelatin Zymography ◽  
Migration And Invasion ◽  
Therapeutic Effects ◽  
Mesenchymal Transition ◽  
Anti Cancer

Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Regorafenib is a multi-kinase inhibitor and the second-line treatment for HCC. Since the PI3K/Akt/mTOR signaling pathway is dysregulated in HCC, we evaluated the therapeutic effects of regorafenib combined with a dual PI3K/mTOR inhibitor BEZ235 in the human HCC cell lines (n = 3). The combined treatment with BEZ235 and regorafenib enhanced the inhibition of cell proliferation and increased the expression of cleaved caspase-3 and cleaved PARP in HCC cells. Moreover, the combined treatment suppressed HCC cell migration and invasion in the transwell assay. Further, the Western blot analyses confirmed the involvement of epithelial-mesenchymal transition (EMT)-related genes such as slug, vimentin, and matrix metalloproteinase (MMP)-9/-2. Additionally, the proteinase activity of MMP-9/-2 was analyzed using gelatin zymography. Furthermore, the inhibition of phosphorylation of the Akt, mTOR, p70S6K, and 4EBP1 after combined treatment was validated using Western blot analysis. Therefore, these results suggest that the combined treatment with BEZ235 and regorafenib benefits patients with HCC.

scholarly journals Synthesis of hybrid anticancer agents based on kinase and histone deacetylase inhibitors

MedChemComm ◽  
2014 ◽  
Vol 5 (12) ◽  
pp. 1829-1833 ◽  
Author(s):  
Hiren Patel ◽  
Irina Chuckowree ◽  
Peter Coxhead ◽  
Matthew Guille ◽  
Minghua Wang ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Anticancer Agents ◽  
Histone Deacetylase Inhibitors ◽  
Kinase Inhibitor

A HDAC, kinase inhibitor hybrid, (Z)-N1-(3-((1H-pyrrol-2-yl)methylene)-2-oxoindolin-5-yl)-N8-hydroxyoctanediamide, 6, showed impressive anticancer action in a number of biochemical and cell-based assays.

scholarly journals Oncopharmacogenomics of Hepatocellular Carcinoma - A Therapy Related Review

2021 ◽  
Vol 17 (5) ◽  
Author(s):  
Prem Ravi Varma P K
Keyword(s):  
Hepatocellular Carcinoma ◽  
Complex Disease ◽  
Kinase Inhibitor ◽  
Current Knowledge ◽  
Clinical Investigation ◽  
Treatment Strategies ◽  
Standard Of Care ◽  
Molecular Classification ◽  
Molecular Pathways ◽  
Molecular Targeted Drug

Hepatocellular carcinoma (HCC) remains a highly complex disease resistant to commonly used chemotherapy and radiotherapy. As the fifth most common cancer worldwide with the third highest mortality rate and very poorly understood molecular pathways driving hepatocarcinogenesis, new treatment strategies are urgently needed for this devastating disease. The multi kinase inhibitor Sorafenib was the first molecular targeted drug in HCC that led to significant survival benefit in patients with advanced tumors. It is the first drug to be considered standard of care for advanced HCC and supports the importance of molecular therapies in the treatment of this cancer. Analysis of genetic and epigenetic alterations as well as different molecular pathways involved in the development of HCC help to identify potential new druggable targets. A variety of novel compounds are already under preclinical or clinical investigation, and accumulating evidence suggests that combination therapy targeting different pathways will potentiate anti-tumoral effects and will become the future therapeutic approach. In addition, the establishment of a robust molecular classification will pave the way for a more personalized treatment scheme in HCC. In this article a review of the current knowledge of the molecular pathogenesis of HCC and an overview of molecular targeted therapies in the management of HCC are provided.

scholarly journals RAF1 expression is correlated with HAF, a parameter of liver computed tomographic perfusion, and may predict the early therapeutic response to sorafenib in advanced hepatocellular carcinoma patients

Open Medicine ◽  
2020 ◽  
Vol 15 (1) ◽  
pp. 167-174
Author(s):  
Ninzi Tian ◽  
Dong Wu ◽  
Ming Tang ◽  
Huichuan Sun ◽  
Yuan Ji ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Therapeutic Response ◽  
Therapeutic Effects ◽  
Advanced Hepatocellular Carcinoma ◽  
Sorafenib Treatment ◽  
Advanced Hcc ◽  
Expression Levels ◽  
Portal Vein Flow ◽  
Tumor Tissues ◽  
Resistant Group

AbstractObjectivesMonitoring the early treatment effect of sorafenib in advanced hepatocellular carcinoma (HCC) patients is a diagnostic challenge. In a previous study, we reported the potential role of liver computed tomography perfusion (CTP) in the assessment of the response to sorafenib therapy in HCC. The present study aims to investigate whether sorafenib-targeted genes is correlated with CTP parameter, and investigate the potential of sorafenib-targeted genes in early prediction of therapeutic response to sorafenib in advanced HCC.MethodsA total of 21 HCC patients were enrolled. Sorafenib was administered orally at a dose of 400 mg twice daily continuously. Treatment response was assessed using modified response evaluation criteria in solid tumors (mRECIST) criteria. CTP scanning was performed before and after two weeks of sorafenib treatment using a 320-detector row CT scanner. The perfusion parameters of portal vein flow (PVF), hepatic artery flow (HAF), and perfusion index (PI) were acquired by CTP. The expression levels of several sorafenib-targeted genes were assayed using real-time quantitative PCR and western blot analysis. Logistic regression was performed to analyze the relationship between HAF values and RAF1 expression levels.ResultsAccording to mRECIST, the disease control rate (CR+PR+SD) of treatment group was 70.5% after two months of treatment. Compared to background controls, tumor tissues exhibited higher HAF. A sorafenib-targeted gene, RAF1 expression, was increased in tumor tissues especially in the sorafenib-resistant group. The sorafenib-resistant group exhibited a significantly higher RAF1 expression and HAF than the sensitive group. Moreover, the RAF1 expression is positively correlated with the HAF value.ConclusionRAF1 expression might predict therapeutic effects of sorafenib in advanced HCC, where RAF1 could potentially serve as a molecular marker for monitoring early therapeutic effects after sorafenib treatment.

scholarly journals Systemic treatment of hepatocellular carcinoma: from sorafenib to combination therapies

2020 ◽  
Vol 7 (2) ◽  
pp. HEP20
Author(s):  
Christoph Roderburg ◽  
Burcin Özdirik ◽  
Alexander Wree ◽  
Münevver Demir ◽  
Frank Tacke
Keyword(s):  
Hepatocellular Carcinoma ◽  
Kinase Inhibitor ◽  
Systemic Treatment ◽  
Checkpoint Inhibitors ◽  
Treatment Strategies ◽  
Predictive Biomarkers ◽  
Current Data ◽  
Advanced Hepatocellular Carcinoma ◽  
Combination Therapies ◽  
Current Standard

For almost a decade, systemic therapy of advanced hepatocellular carcinoma (HCC) was limited to the tyrosine kinase inhibitor (TKI) sorafenib. Different agents including checkpoint inhibitors, TKIs and anti-VEGFR antibodies demonstrated efficacy in treatment. For the first time, the combination of atezolizumab and bevacizumab, a first-line treatment that is superior to the current standard was identified, potentially changing the way we treat HCC. In this review, we summarize current data on systemic treatment of patients with advanced HCC, focusing on combination therapies comprising immune checkpoint inhibitors, TKIs and locoregional therapies. We elucidate findings from recent trials and discuss such challenges as the lack of predictive biomarkers for identification of subgroups that will benefit from novel treatment strategies.

Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

2020 ◽  
Vol 19 (17) ◽  
pp. 2120-2129 ◽  
Author(s):  
Sakineh Dadashpour ◽  
Tuba T. Küçükkılınç ◽  
Ayse Ercan ◽  
Seyed J. Hosseinimehr ◽  
Nima Naderi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Anticancer Agents ◽  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Biological Evaluation ◽  
Kinase Assay ◽  
Drug Candidate ◽  
Surface Receptors ◽  
Anticancer Mechanism

Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer. Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents. Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells. Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition. Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

Histone Deacetylases and their Inhibitors in Colorectal Cancer Therapy: Current Evidence and Future Considerations

2021 ◽  
Vol 28 ◽  
Author(s):  
Nikolaos Garmpis ◽  
Christos Damaskos ◽  
Anna Garmpi ◽  
Afroditi Nonni ◽  
Vasiliki E. Georgakopoulou ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Anticancer Agents ◽  
Histone Deacetylases ◽  
Hdac Inhibitors ◽  
Current Evidence ◽  
Epigenetic Factors ◽  
Genetic Changes ◽  
Regulate Gene Expression ◽  
Molecular Pathophysiology

: Colorectal cancer (CRC) comprises a heterogeneous group of gastrointestinal tract tumors. It is a multifactorial disease, and a plethora of distinct factors are involved in its pathogenesis and pathophysiology. The development of CRC is not limited to genetic changes, but epigenetic and environmental factors are also involved. Among the epigenetic factors, histone deacetylases (HDACs), a group of epigenetic enzymes that regulate gene expression, have been reported to be over-expressed in CRC. HDACs and their inhibitors seem to play an important role in the molecular pathophysiology of CRC. The aim of this review was to define the role of HDAC inhibitors as potential anticancer agents against CRC.

Discovery of class I histone deacetylase inhibitors based on romidpesin with promising selectivity for cancer cells

2020 ◽  
Vol 12 (4) ◽  
pp. 311-323
Author(s):  
Kuojun Zhang ◽  
Yiwu Yao ◽  
Zhengchao Tu ◽  
Chenzhong Liao ◽  
Zhen Wang ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Anticancer Agents ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Histone Deacetylase Inhibitors ◽  
Therapeutic Potential ◽  
Selective Inhibition ◽  
Class I ◽  
Antitumor Effects ◽  
Synthesis Strategy

Aim: Class I histone deacetylases (HDACs) are considered to be promising anticancer targets, but selective inhibition of class I HDAC isoforms remains a challenge. Methods & results: Previously, we obtained a selective class I HDAC inhibitor 9 based on a macrocyclic HDAC inhibitor Romidpesin. As our continuous efforts, a library of novel cyclicdepsipeptides based on 9 was established using a convergent synthesis strategy. The most active compounds 10, 16 and 19 selectively inhibit class I HDACs and exhibit promising nanomolar antiproliferative activities against several cancer cell lines with excellent selectivity toward cancer cells over normal cells. Besides, compound 10 demonstrates excellent antitumor effects in human prostate carcinoma PC3 xenograft models with no observed toxicity. Conclusion: These cyclicdepsipeptides show great therapeutic potential as novel anticancer agents for clinical translation.

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