GSK-3 in liver diseases: Friend or foe?

Liver diseases, including hepatitis due to hepatitis B or C virus infection, non-alcoholic fatty liver disease, and hepatocellular carcinoma pose major challenges for overall health due to limited curative treatment options. Thus, there is an urgent need to develop new therapeutic strategies for the treatment of these diseases. A better understanding of the signaling pathways involved in the pathogenesis of liver diseases can help to improve the efficacy of emerging therapies, mainly based on pharmacological approaches, which influence one or more specific molecules involved in key signal transduction pathways. These emerging therapies are very promising for the prevention and treatment of …

Hepatic and circulating levels of PCSK9 in morbidly obese patients: Relation with severity of liver steatosis

Non-alcoholic fatty liver disease (NAFLD) is becoming the main cause of liver disease in Western countries, especially in morbidly obese patients (MOPs). The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been recently studied because of its possible involvement in the pathogenesis of NAFLD, but its role, at least in MOPs, is still controversial. The aim of this study was to clarify the correlation between the circulating levels of the PCSK9 protein (cPCSK9) and its hepatic expression with the severity of liver damage in a population of MOPs with NAFLD undergoing bariatric surgery. PCSK9 mRNA was positively correlated with FASN, PPARγ and PPARα mRNAs, while no significant differe…

New landscapes and horizons in hepatocellular carcinoma therapy

Hepatocellular carcinoma (HCC), is the sixth most frequent form of cancer and leads to the fourth highest number of deaths each year. HCC results from a combination of environmental factors and aging as there are driver mutations at oncogenes which occur during aging. Most of HCCs are diagnosed at advanced stage preventing curative therapies. Treatment in advanced stage is a challenging and pressing problem, and novel and well-tolerated therapies are urgently needed. We will discuss further advances beyond sorafenib that target additional signaling pathways and immune checkpoint proteins. The scenario of possible systemic therapies for patients with advanced HCC has changed dramatically in …

NUPR1, a new target in liver cancer: implication in controlling cell growth, migration, invasion and sorafenib resistance

AbstractSorafenib, an oral multikinase inhibitor, is the only approved agent for the treatment of advanced hepatocellular carcinoma (HCC). However, its benefits are modest, and as its mechanisms of action remain elusive, a better understanding of its anticancer effects is needed. Based on our previous study results, we investigated here the implication of the nuclear protein 1 (NUPR1) in HCC and its role in sorafenib treatment. NUPR1 is a stress-inducible protein that is overexpressed in various malignancies, but its role in HCC is not yet fully understood. We found that NUPR1 expression was significantly higher in primary human HCC samples than in the normal liver. Knockdown of NUPR1 signi…

Potential Uses of Olive Oil Secoiridoids for the Prevention and Treatment of Cancer: A Narrative Review of Preclinical Studies

The Mediterranean diet (MD) is a combination of foods mainly rich in antioxidants and anti-inflammatory nutrients that have been shown to have many health-enhancing effects. Extra-virgin olive oil (EVOO) is an important component of the MD. The importance of EVOO can be attributed to phenolic compounds, represented by phenolic alcohols, hydroxytyrosol, and tyrosol, and to secoiridoids, which include oleocanthal, oleacein, oleuropein, and ligstroside (along with the aglycone and glycosidic derivatives of the latter two). Each secoiridoid has been studied and characterized, and their effects on human health have been documented by several studies. Secoiridoids have antioxidant, anti-inflammat…

Biocompatible Lipid Nanoparticles as Carriers to Improve Curcumin Efficacy in Ovarian Cancer Treatment

Curcumin is a natural molecule with proved anticancer efficacy on several human cancer cell lines. However, its clinical application has been limited due to its poor bioavailability. Nanocarrier-based drug delivery approaches could make curcumin dispersible in aqueous media, thus overtaking the limits of its low solubility. The aim of this study was to increase the bioavailability and the antitumoral activity of curcumin, by entrapping it into nanostructured lipid carriers (NLCs). For this purpose here we describe the preparation and characterization of three kinds of curcumin-loaded NLCs. The nanosystems allowed the achievement of a controlled release of curcumin, the amounts of curcumin r…

Lipid nanocarriers containing sorafenib inhibit colonies formation in human hepatocarcinoma cells

Here, the potential of two nanostructured lipid carriers (NLC) for controlled release of sorafenib was evaluated. The obtained systems showed characteristics suitable as drug delivery systems for the treatment of hepatocellular carcinoma (HCC) through parenteral administration. The use of a mixture between a solid lipid (tripalmitin) with a liquid lipid (Captex 355 EP/NF or Miglyol 812) to prepare NLC systems could give a higher drug loading capacity and a longer term stability during storage than that obtained by using only solid lipids. The obtained nanoparticles showed a nanometer size and high negative zeta potential values. Scansion electron microscopy (SEM) of the sorafenib loaded NLC…

Apoptosis and cell growth arrest in A375 human melanoma cells by diorganotin(IV) and triorganotin(IV) complexes of [meso-Tetra(4-sulfonatophenyl)porphine] manganese(III)chloride

In previous studies we have demonstrated that two derivatives of meso-Tetra(4-sulfonatophenyl)porphine (TPPS), (Bu2Sn)2TPPS and (Bu3Sn)4TPPS, cause apoptotic death of A375 melanoma cells and, at lower concentrations, arrest of cell proliferation. In the present study, we examined if the manganese metal inside the porphyrin cavity could improve the efficacy of this class of compounds. Thus, [meso- Tetra(4-sulfonatophenyl)porphine]Mn(III)Cl (=MnTPPS) derivatives, namely (Me2Sn)2MnTPPS, (Bu2Sn)2MnTPPS, (Me3Sn)4MnTPPS and (Bu3Sn)4MnTPPS, were tested on the A375 human melanoma cell line. A cytotoxicity assay showed that (Bu2Sn)2MnTPPS and (Bu3Sn)4MnTPPS were highly cytotoxic by inducing apoptosi…

Cationic solid lipid nanoparticles complexed with genetic material for liver tumor treatment

Concept Gene therapy is a growing field of medicine with great potential for the treatment of several diseases and it is based on the delivery of nucleic acids (DNA, RNA, etc.,) to specific cells. To achieve their therapeutic effects, the nucleic acids need to cross several biological barriers and be protected from the degradation by nucleases, present in biological fluids and intracellular compartments, to successfully gain access to their intracellular targets. To overcome these hurdles, it is necessary to deliver the genetic material with biocompatible carriers able to facilitate its translocation across the cell membranes and protect it from being degraded while circulating in the blood…

The Role of GSK-3 in Cancer Immunotherapy: GSK-3 Inhibitors as a New Frontier in Cancer Treatment

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified because of its key role in the regulation of glycogen synthesis. However, it is now well-established that GSK-3 performs critical functions in many cellular processes, such as apoptosis, tumor growth, cell invasion, and metastasis. Aberrant GSK-3 activity has been associated with many human diseases, including cancer, highlighting its potential therapeutic relevance as a target for anticancer therapy. Recently, newly emerging data have demonstrated the pivotal role of GSK-3 in the anticancer immune response. In the last few years, many GSK-3 inhibitors have been developed, and some are currently being te…

Preclinical evaluation of antitumor activity of the proteasome inhibitor MLN2238 (ixazomib) in hepatocellular carcinoma cells

AbstractHepatocellular carcinoma (HCC) is one of the common malignancies and is an increasingly important cause of cancer death worldwide. Surgery, chemotherapy, and radiation therapy extend the 5-year survival limit in HCC patients by only 6%. Therefore, there is a need to develop new therapeutic approaches for the treatment of this disease. The orally bioavailable proteasome inhibitor MLN2238 (ixazomib) has been demonstrated to have anticancer activity. In the present study, we investigated the preclinical therapeutic efficacy of MLN2238 in HCC cells through in vitro and in vivo models, and examined its molecular mechanisms of action. MLN2238 inhibited cell viability in human HCC cells He…

Delivery of shNupr1 plasmid by solid lipid nanoparticles reduces the expression of Nupr1 gene in hepatocellular carcinoma cells

A PTEN inhibitor displays preclinical activity against hepatocarcinoma cells

Phosphatase and tensin homolog (PTEN) gene is considered a tumor suppressor gene. However, PTEN mutations rarely occur in hepatocellular carcinoma (HCC), whereas heterozygosity of PTEN, resulting in reduced PTEN expression, has been observed in 32–44% of HCC patients. In the present study, we investigated the effects of the small molecule PTEN inhibitor VO-OHpic in HCC cells. VO-OHpic inhibited cell viability, cell proliferation and colony formation, and induced senescence-associated β-galactosidase activity in Hep3B (low PTEN expression) and to a lesser extent in PLC/PRF/5 (high PTEN expression) cells, but not in PTEN-negative SNU475 cells. VO-OHpic synergistically inhibited cell viability…

Delivery of shRNA plasmid DNA by cationic solid lipid nanoparticles for gene silencing in human hepatocarcinoma cells

Effects of organotin(IV)(metal-sulfonatophenyl)porphinates on the growth of A375 human melanoma cells

Two single nucleotide polymorphisms in the MICA gene and sMICA plasma levels are associated with hepatocellular carcinoma development in an Italian population of HCV related liver cirrhosis

Background & Aims: We investigated the relationships between MICA polymorphisms, sMICA levels and hepatocellular carcinoma (HCC) risk in HCC patients with chronic hepatitis C virus (HCV) infection. Methods.154 HCV-related HCC cases, 93 HCV-related liver cirrhosis (LC) cases and 244 healthy controls were genotyped using KASPTM SNP method. Levels of plasma soluble MICA (sMICA) were measured in 132 HCC, 90 LC patients and in 78 controls. Results. Genotyping of MICA rs2596542 showed that G/G genotype was significantly more frequent in HCC than in controls and in HCC than in LC patients. As for MICA rs2596538 allele C and C/C genotype were significantly more frequent in HCC than in controls …

Cationic Solid Lipid Nanoparticles (SLN) for shNupr1 plasmid delivery in the treatment of hepatocellular carcinoma (HCC)

Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3β in HCC remain controversial, several studies suggested a possible role of GSK-3β as a tumor …

RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma

Introduction: Hepatocellular carcinoma (HCC) is a significant problem globally because of viral infections and the increasing incidence of obesity and fatty liver disease. However, it is difficult to treat because its inherent genetic heterogeneity results in activation of numerous signaling pathways. Kinases have been targeted for decades with varying results, but the development of therapeutic resistance is a major challenge. Areas covered: The key roles of the RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1, TP53 microRNAs (miRs) as therapeutic targets are discussed and we suggests novel approaches for targeting miRs or their downstream targets to combat HCC. We performed literature searches using…

Association between MICA Gene Variants and the Risk of Hepatitis C Virus-Induced Hepatocellular Cancer in a Sicilian Population Sample

There are currently no biomarkers that predict hepatocellular carcinoma (HCC) risk in patients with hepatitis C virus (HCV)-related cirrhosis. We investigated the relationships among major histocompatibility complex (MHC) class I chain-related gene A (MICA) polymorphisms, plasma levels of soluble MICA (sMICA), and HCC risk in patients with HCV-related HCC. One hundred fifty-four HCV-related HCC patients, 93 HCV-related liver cirrhosis (LC) cases, and 244 healthy controls, all sampled from the native Sicilian population, were genotyped using the KASP™ single-nucleotide polymorphism genotyping method. The MICA rs2596542 polymorphism showed that the G/G genotype was significantly more frequent…

CATIONIC SLN AS TARGETING GENE DELIVERY SYSTEMS FOR HEPATOCELLULAR CARCINOMA

Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third leading cause of cancer-related deaths. In the United States, the incidence of HCC has almost tripled during the past two decades and HCC has become one of the fastest growing cancers. While surgical removal of tumor tissues is an effective approach to protect relatively healthy liver tissue, it is only applicable to a small subset of HCC patients with specific pathological conditions, such as confined tumor mass without portal hypertension. Therefore, there is an urgent need to develop novel therapeutic strategies to treat this deadly disease. Systemic tumor-targeted gene delivery is attracting increasin…

Oleocanthal exerts antitumor effects on human liver and colon cancer cells through ROS generation

The beneficial health properties of the Mediterranean diet are well recognized. The principle source of fat in Mediterranean diet is extra-virgin olive oil (EVOO). Oleocanthal (OC) is a naturally occurring minor phenolic compound isolated from EVOO, which has shown a potent anti-inflammatory activity, by means of its ability to inhibit the cyclooxygenase (COX) enzymes COX-1 and COX-2. A large body of evidence indicates that phenols exhibit anticancer activities. The aim of the present study was to evaluate the potential anticancer effects of OC in hepatocellular carcinoma (HCC) and colorectal carcinoma (CRC) models. A panel of human HCC (HepG2, Huh7, Hep3B and PLC/PRF/5) and CRC (HT29, SW48…

GDF11 induces mild hepatic fibrosis independent of metabolic health

BACKGROUND & AIMS: Growth Differentiation Factor 11 (GDF11) is an anti-aging factor, yet its role in liver diseases is not established. We evaluated the role of GDF11 in healthy conditions and in the transition from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). RESULTS: GDF11 mRNA levels positively correlated with NAFLD activity score and with CPT1, SREBP, PPAR? and Col1A1 mRNA levels, and associated to portal fibrosis, in morbidly obese patients with NAFLD/NASH. GDF11-treated mice showed mildly exacerbated hepatic collagen deposition, accompanied by weight loss and without changes in liver steatosis or inflammation. GDF11 triggered ALK5-dependent SMAD2/…

NUPR1 protects liver from lipotoxic injury by improving the endoplasmic reticulum stress response

AbstractBackground and AimsNon-alcoholic fatty liver disease and related hepatic syndromes affect up to one third of the adult population. The molecular mechanisms underlying NAFL etiology remain elusive. Nuclear Protein 1 (NUPR1) expression increases upon cell injury in all organs and recently we report its active participation in the activation of the Unfolded Protein Response (UPR). The UPR typically maintains protein homeostasis, but downstream mediators of the pathway regulate metabolic functions, including lipid metabolism. NUPR1 and UPR increase have been reported in obesity and liver pathologies and the goal of this study was to investigate the roles of NUPR1 in this context.Methods…

Targeting HSP90 with the small molecule inhibitor AUY922 (luminespib) as a treatment strategy against hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a highly malignant tumor that responds very poorly to existing therapies, most probably due to its extraordinary inter- and intra-tumor molecular heterogeneity. The modest therapeutic response to molecular targeted agents underlines the need for new therapeutic approaches for HCC. In our study, we took advantage of well-characterized human HCC cell lines, differing in transcriptomic subtypes, DNA mutation and amplification alterations, reflecting the heterogeneity of primary HCCs, to provide a preclinical evaluation of the specific heat shock protein 90 (HSP90) inhibitor AUY922 (luminespib). Indeed, HSP90 is highly expressed in different tumor types, but it…

Nanoparticles of a polyaspartamide-based brush copolymer for modified release of sorafenib: In vitro and in vivo evaluation.

Abstract In this paper, we describe the preparation of polymeric nanoparticles (NPs) loaded with sorafenib for the treatment of hepatocellular carcinoma (HCC). A synthetic brush copolymer, named PHEA-BIB-ButMA (PBB), was synthesized by Atom Trasnfer Radical Polymerization (ATRP) starting from the α-poly( N -2-hydroxyethyl)- d , l -aspartamide (PHEA) and poly butyl methacrylate (ButMA). Empty and sorafenib loaded PBB NPs were, then, produced by using a dialysis method and showed spherical morphology, colloidal size, negative ζ potential and the ability to allow a sustained sorafenib release in physiological environment. Sorafenib loaded PBB NPs were tested in vitro on HCC cells in order to e…

From Targets to Targeted Therapies in Hepatocellular Carcinoma

The Prevalence of NAFLD and Fibrosis in Bariatric Surgery Patients and the Reliability of Noninvasive Diagnostic Methods

Background. Bariatric surgery patients have a higher prevalence of nonalcoholic fatty liver (NAFL) than the general population; however, its assessment and the accurate staging of fibrosis are often complicated because noninvasive tests are not very accurate in patients with morbid obesity, and liver biopsy cannot be performed as a routine exam. The aim of this study was to evaluate (A) the histological prevalence of NAFL, nonalcoholic steatohepatitis (NASH), and fibrosis in patients undergoing bariatric surgery; (B) the reliability of ultrasound (US) in diagnosing NAFL; and (C) the reliability of various fibrosis scoring systems for defining fibrosis. Methods. US and intraoperative liver b…

Hepatocellular Carcinoma: A Difficult Cancer to Treat

Hepatocellular carcinoma (HCC) is a very peculiar cancer because it presents several molecular alterations linked to the activation of survival and antiapoptotic signal pathways that are protein in form and not easily targetable by even the newest targeted therapies. In addition, it is almost always a consequence of liver cirrhosis, a serious disease condition in which several drugs are often not tolerated. This is why the study of HCC was such a challenge for Professor Natale D'Alessandro, to whom this work is dedicated, during the latter years of his career. The aim of this review is to summarize studies on different molecules involved in the development, progression, and chemoresistance …

The NUPR1/p73 axis contributes to sorafenib resistance in hepatocellular carcinoma

The multikinase inhibitor sorafenib was the first drug approved by the FDA for treating patients with advanced hepatocellular carcinoma (HCC). However, sorafenib resistance remains a major challenge for improving the effectiveness of HCC treatment. Previously, we identified several genes modulated after sorafenib treatment of human HCC cells, including the stress-inducible nuclear protein 1 (NUPR1) gene. Multiple studies have shown that NUPR1 regulates autophagy, apoptosis, and chemoresistance. Here, we demonstrate that treatment of HCC cells with sorafenib resulted in the activation of autophagic flux. NUPR1 knock-down (KD) in HCC cells was associated with increased p62 expression, suggest…

A PTEN inhibitor displays preclinical activity against hepatocarcinoma cells

Phosphatase and tensin homolog (PTEN) gene is considered a tumor suppressor gene. However, PTEN mutations rarely occur in hepatocellular carcinoma (HCC), whereas heterozygosity of PTEN, resulting in reduced PTEN expression, has been observed in 32–44% of HCC patients. In the present study, we investigated the effects of the small molecule PTEN inhibitor VO-OHpic in HCC cells. VO-OHpic inhibited cell viability, cell proliferation and colony formation, and induced senescence-associated β-galactosidase activity in Hep3B (low PTEN expression) and to a lesser extent in PLC/PRF/5 (high PTEN expression) cells, but not in PTEN-negative SNU475 cells. VO-OHpic synergistically inhibited cell viability…