Development of Novel Imipridones with Alkyne- and Triazole-Linked Warheads on the Tricyclic Skeleton, Showing Superior Ability to Eradicate PANC-1 and Fadu Cells Compared to ONC201.

Our ongoing research focuses on the development of new imipridone derivatives. We aim to design compounds that can completely and selectively eradicate cancer cells after relatively short treatment. We have synthetized systematically designed novel hybrids and evaluated their antiproliferative activity against PANC-1 and Fadu cell lines.

Potential Prognostic Role of Protein Kinase D Isoforms in Head and Neck Cancers.

Head and neck squamous cell carcinomas (HNSCC) are among the most common malignancies in men worldwide. Nevertheless, their clinical management is hampered by the limited availability of reliable predictive and prognostic biomarkers. Protein kinase D (PKD) isoforms contribute to major cellular processes.

Severity Ranking of Missense and Frameshift Genetic Variants in SCD1 by In Silico and In Vitro Functional Analysis.

Background: A considerable proportion of the symptoms associated with excessive dietary intake can be attributed to systemic imbalances in lipid metabolism. The prominent toxicity of saturated fatty acids has been repeatedly demonstrated and sheds light on the protective role of stearoyl-CoA desaturase-1 (SCD1), the key enzyme for fatty acid desaturation. SCD1 protein expression is regulated at the levels of transcription, translation, and degradation.

Allele-specific effect of various dietary fatty acids and ETS1 transcription factor on SCD1 expression.

Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed.

Role of Extracellular Vesicles in Liver Diseases.

Extracellular vesicles (EVs) are cell-derived membrane structures that are formed by budding from the plasma membrane or originate from the endosomal system. These microparticles (100 nm-100 µm) or nanoparticles (>100 nm) can transport complex cargos to other cells and, thus, provide communication and intercellular regulation. Various cells, such as hepatocytes, liver sinusoidal endothelial cells (LSECs) or hepatic stellate cells (HSCs), secrete and take up EVs in the healthy liver, and the amount, size and content of these vesicles are markedly altered under pathophysiological conditions.

Molecular Basis of Unequal Alternative Splicing of Human SCD5 and Its Alteration by Natural Genetic Variations.

Alternative splicing (AS) is a major means of post-transcriptional control of gene expression, and provides a dynamic versatility of protein isoforms. Cancer-related AS disorders have diagnostic, prognostic and therapeutic values. Changes in the expression and AS of human stearoyl-CoA desaturase-5 (SCD5) are promising specific tumor markers, although the transcript variants (TVs) of the gene have not yet been confirmed.

Novel Erlotinib-Chalcone Hybrids Diminish Resistance in Head and Neck Cancer by Inducing Multiple Cell Death Mechanisms.

In a search for novel therapeutic options for head and neck squamous cell carcinomas (HNSCCs) generally treated with limited therapeutic success, we synthesized a series of novel erlotinib-chalcone molecular hybrids with 1,2,3-triazole and alkyne linkers and evaluated them for their anticancer activity on Fadu, Detroit 562 and SCC-25 HNSCC cell lines. Time- and dose-dependent cell viability measurements disclosed a significantly increased efficiency of the hybrids compared to the 1:1 combination of erlotinib and a reference chalcone. The clonogenic assay demonstrated that hybrids eradicate HNSCC cells in low micromolar concentrations.

MEK Is a Potential Indirect Target in Subtypes of Head and Neck Cancers.

The poor prognosis of head-and-neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable prognostic and predictive markers. The Ras/Raf/MEK/ERK signaling pathway is often activated by overexpressed epidermal growth factor receptor (EGFR) and stimulates the progression of HNSCCs. Our research was performed on three human papillomavirus (HPV)-negative HNSCC-cell lines: Detroit 562, FaDu and SCC25.

Protein Kinase D3 (PKD3) Requires Hsp90 for Stability and Promotion of Prostate Cancer Cell Migration.

Prostate cancer metastasis is a significant cause of mortality in men. PKD3 facilitates tumor growth and metastasis, however, its regulation is largely unclear. The Hsp90 chaperone stabilizes an array of signaling client proteins, thus is an enabler of the malignant phenotype.

A Single Nucleotide Polymorphism (rs3811792) Affecting Human Promoter Activity Is Associated with Diabetes Mellitus.

The combined prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus is 10.5% worldwide and this is constantly increasing. The pathophysiology of the diseases include disturbances of the lipid metabolism, in which acyl-CoA desaturases play a central role as they synthesize unsaturated fatty acids, thereby providing protection against lipotoxicity.

Different Metabolism and Toxicity of TRANS Fatty Acids, Elaidate and Vaccenate Compared to Cis-Oleate in HepG2 Cells.

Trans fatty acids (TFAs) are not synthesized in the human body but are generally ingested in substantial amounts. The widespread view that TFAs, particularly those of industrial origin, are unhealthy and contribute to obesity, cardiovascular diseases and diabetes is based mostly on in vivo studies, and the underlying molecular mechanisms remain to be elucidated. Here, we used a hepatoma model of palmitate-induced lipotoxicity to compare the metabolism and effects of the representative industrial and ruminant TFAs, elaidate and vaccenate, respectively, with those of cis-oleate.

Molecular Mechanisms Underlying the Elevated Expression of a Potentially Type 2 Diabetes Mellitus Associated SCD1 Variant.

Disturbances in lipid metabolism related to excessive food intake and sedentary lifestyle are among major risk of various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) has an essential role in these diseases, as it catalyzes the synthesis of unsaturated fatty acids, both supplying for fat storage and contributing to cellular defense against saturated fatty acid toxicity. Recent studies show that increased activity or over-expression of SCD1 is one of the contributing factors for type 2 diabetes mellitus (T2DM).

Synthesis and Antiproliferative Activity of Novel Imipridone-Ferrocene Hybrids with Triazole and Alkyne Linkers.

Imipridones, including ONC201, ONC206 and ONC212 (which are emblematic members of this class of compounds developed by Oncoceutics) constitute a novel class of anticancer agents, with promising results in clinical trials. With the aim of increasing the ROS (reactive oxygen species) responsivity of the synthesized molecules, a set of novel ferrocene-imipridone hybrids were designed and synthesized. Our strategy was motivated by the documented interplay between the imipridone-triggered activation of TRAIL (the tumor necrosis factor-related apoptosis-inducing ligand) and mitochondrial ClpP (Caseinolytic protease P) and the ROS-mediated effect of ferrocene-containing compounds.

Effect of cis- and trans-Monounsaturated Fatty Acids on Palmitate Toxicity and on Palmitate-induced Accumulation of Ceramides and Diglycerides.

Dietary trans fatty acids (TFAs) have been implicated in serious health risks, yet little is known about their cellular effects and metabolism. We aim to undertake an in vitro comparison of two representative TFAs (elaidate and vaccenate) to the best-characterized endogenous cis-unsaturated FA (oleate). The present study addresses the possible protective action of TFAs on palmitate-treated RINm5F insulinoma cells with special regards to apoptosis, endoplasmic reticulum stress and the underlying ceramide and diglyceride (DG) accumulation.

The Potential Impact of Connexin 43 Expression on Bcl-2 Protein Level and Taxane Sensitivity in Head and Neck Cancers-In Vitro Studies.

The poor prognosis of head and neck squamous cell carcinoma (HNSCC) is partly due to the lack of reliable predictive markers. Connexin 43 (Cx43) protein and its cell-communication channels have been assigned tumor suppressor functions while the anti-apoptotic Bcl-2 (B-cell lymphoma-2) protein has been associated with negative prognostic significance in cancer. This study aimed to test the role of Cx43 protein on Bcl-2 expression, tumor progression and response to taxane-based treatment in HNSCC.

Novel Crizotinib-GnRH Conjugates Revealed the Significance of Lysosomal Trapping in GnRH-Based Drug Delivery Systems.

Several promising anti-cancer drug-GnRH (gonadotropin-releasing hormone) conjugates have been developed in the last two decades, although none of them have been approved for clinical use yet. Crizotinib is an effective multi-target kinase inhibitor, approved against anaplastic lymphoma kinase (ALK)- or ROS proto-oncogene 1 (ROS-1)-positive non-small cell lung carcinoma (NSCLC); however, its application is accompanied by serious side effects. In order to deliver crizotinib selectively into the tumor cells, we synthesized novel crizotinib analogues and conjugated them to a [d-Lys]-GnRH-I targeting peptide.

BGP-15 Protects Mitochondria in Acute, Acetaminophen Overdose Induced Liver Injury.

Acetaminophen (APAP) induced hepatotoxicity involves activation of c-Jun amino-terminal kinase (JNK), mitochondrial damage and ER stress. BGP-15, a hydroximic acid derivative, has been reported to have hepatoprotective effects in APAP overdose induced liver damage. Effect of BGP-15 was further investigated on mitochondria in APAP-overdose induced acute liver injury in mice.

Cellular toxicity of dietary trans fatty acids and its correlation with ceramide and diglyceride accumulation.

High fatty acid (FA) levels are deleterious to pancreatic β-cells, largely due to the accumulation of biosynthetic lipid intermediates, such as ceramides and diglycerides, which induce ER stress and apoptosis. Toxicity of palmitate (16:0) and oleate (18:1 cis-Δ) has been widely investigated, while very little data is available on the cell damages caused by elaidate (18:1 trans-Δ) and vaccenate (18:1 trans-Δ), although the potential health effects of these dietary trans fatty acids (TFAs) received great publicity. We compared the effects of these four FAs on cell viability, apoptosis, ER stress, JNK phosphorylation and autophagy as well as on ceramide and diglyceride contents in RINm5F insulinoma cells.

Microsomal pre-receptor cortisol production is inhibited by resveratrol and epigallocatechin gallate through different mechanisms.

Local activation of cortisol in hormone target tissues is a major determinant of glucocorticoid effect. Disorders in this peripheral cortisol metabolism play an important role in the development of metabolic diseases, such as obesity or type 2 diabetes mellitus. Hence, dietary factors influencing the activity of the involved enzymes can have major impacts on the risk of the above diseases.

Epigallocatechin-3-Gallate (EGCG) Promotes Autophagy-Dependent Survival via Influencing the Balance of mTOR-AMPK Pathways upon Endoplasmic Reticulum Stress.

The maintenance of cellular homeostasis is largely dependent on the ability of cells to give an adequate response to various internal and external stimuli. We have recently proposed that the life-and-death decision in endoplasmic reticulum (ER) stress response is defined by a crosstalk between autophagy, apoptosis, and mTOR-AMPK pathways, where the transient switch from autophagy-dependent survival to apoptotic cell death is controlled by GADD34. The aim of the present study was to investigate the role of epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, in promoting autophagy-dependent survival and to verify the key role in connecting GADD34 with mTOR-AMPK pathways upon prolonged ER stress.

[Hyper-free fatty acidemia - insulin resistance and β-cell death].

The increasing prevalence of type 2 diabetes correlates with the rapid spread of obesity worldwide. Adipocytes are strained by the demand of excessive storage, and the local inflammation accelerates triglyceride turnover, which elevates the plasma levels of free fatty acids. Sustained hyper-free fatty acidemia leads to disturbances in cellular functions (lipotoxicity) or even to programmed cell death.

Cytosolic localization of NADH cytochrome b₅ oxidoreductase (Ncb5or).

Acyl-CoA desaturation in the endoplasmic reticulum (ER) membrane depends on cytosolic NADH or NADPH, whereas NADPH in the ER lumen is utilized by prereceptor glucocorticoid production. It was assumed that NADH cytochrome b5 oxidoreductase (Ncb5or) might connect Acyl-CoA desaturation to ER luminal redox. We aimed to clarify the ambiguous compartmentalization of Ncb5or and test the possible effect of stearoyl-CoA on microsomal NADPH level.

Novel compounds reducing IRS-1 serine phosphorylation for treatment of diabetes.

Activation of various interacting stress kinases, particularly the c-Jun N-terminal kinases (JNK), and a concomitant phosphorylation of insulin receptor substrate 1 (IRS-1) at serine 307 play a central role both in insulin resistance and in β-cell dysfunction. IRS-1 phosphorylation is stimulated by elevated free fatty acid levels through different pathways in obesity. A series of novel pyrido[2,3-d]pyrimidin-7-one derivatives were synthesized as potential antidiabetic agents, preventing IRS-1 phosphorylation at serine 307 in a cellular model of lipotoxicity and type 2 diabetes.