Exploring the impact of polyvinylidenefluoride membrane physical properties on the enrichment efficacy of microfluidic electro-membrane extraction of acidic drugs.

Membrane technology has revolutionized various fields with its energy efficiency, versatility, user-friendliness, and adaptability. This study introduces a microfluidic chip, comprised of silicone rubber and polymethylmethacrylate (PMMA) sheets to explore the impacts of polymeric support morphology on electro-membrane extraction efficiency, representing a pioneering exploration in this field. In this research, three polyvinylidenefluoride (PVDF) membranes with distinct pore sizes were fabricated and their characteristics were assessed through field-emission scanning electron microscopy (FESEM), and atomic force microscopy (AFM). This investigation centers on the extraction of three widely prescribed non-steroidal anti-inflammatory drugs: aspirin (ASA), naproxen (NAP), and ibuprofen (IBU). Quantitative parameters in the extraction process including voltage, donor phase flow rate, and acceptor phase composition were optimized, considering the type of membrane as a qualitative factor. To assess the performance of the fabricated PVDF membranes, a comparative analysis with a commercially available Polypropylene (PP) membrane was conducted. Efficient enrichment factors of 30.86, 23.15, and 21.06 were attained for ASA, NAP, and IBU, respectively, from urine samples under optimal conditions using the optimum PVDF membrane. Significantly, the choice of the ideal membrane amplified the purification levels of ASA, NAP, and IBU by factors of 1.6, 7.5, and 40, respectively.

Selective binding of cationic fibrinogen-mimicking chitosan nanoparticles to activated platelets and efficient drug release for antithrombotic therapy.

Thrombosis is the main cause of catastrophic events including ischemic stroke, myocardial infarction and pulmonary embolism. Acetylsalicylic acid (ASA) therapy offers a desirable approach to antithrombosis through a reduction of platelet reactivity. However, major bleeding complications, severe off-target side effects, and resistance or nonresponse to ASA greatly attenuate its clinical outcomes. Herein, we report a cationic fibrinogen-mimicking nanoparticle, denoted as ASA-RGD-CS@TPP, to achieve activated-platelet-targeted delivery and efficient release of ASA for safer and more effective antithrombotic therapy. This biomimetic antithrombotic system was prepared by one-pot ionic gelation between cationic arginine-glycine-aspartic acid (RGD)-grafted chitosan (RGD-CS) and anionic tripolyphosphate (TPP). The platform exhibited selective binding to activated platelets, leading to efficient release of ASA and subsequent attenuation of platelet functions, including the remarkable inhibition of platelet aggregation through a potent blockage of cyclooxygenase-1 (COX-1). After intravenous administration, ASA-RGD-CS@TPP displayed significantly prolonged circulation time and successful prevention of thrombosis in a mouse model. ASA-RGD-CS@TPP was demonstrated to significantly enhance antithrombotic therapy while showing minimal coagulation and hemorrhagic risks and excellent biocompatibility in vivo as compared to free ASA. This platform provides a simple, safe, effective and targeted strategy for the development of antithrombotic nanomedicines.

Understanding the Roles of Excipients in Moisture Management in Solid Dosage Forms.

Excipients are ubiquitous in pharmaceutical products, and often, they can also play a critical role in maintaining product quality. For a product containing a moisture-sensitive drug, moisture can be deleterious to the product stability during storage. Therefore, using excipients that interact with moisture in situ can potentially alleviate product stability issues. In this study, the interactive behavior of starch with moisture was augmented by coprocessing maize starch with sodium chloride (NaCl) or magnesium nitrate hexahydrate [Mg(NO3)2·6H2O] at different concentrations (5 and 10%, w/w). The effect of the formulation on drug stability was assessed through the degradation of acetylsalicylic acid, which was used as the model drug. The results showed that coprocessing of the starch with either NaCl or Mg(NO3)2·6H2O impacted the number of water molecule binding sites on the starch and how the sorbed moisture was distributed. The coprocessed excipients also resulted in lower drug degradation and lesser changes in tablet tensile strength during post-compaction storage. However, corresponding tablet formulations containing physical mixtures of starch and salts did not yield promising outcomes. This study demonstrated the advantageous concomitant use of common excipients by coprocessing to synergistically mitigate the adverse effects of moisture and promote product stability when formulating a moisture-sensitive drug. In addition, the findings could help to improve the understanding of moisture-excipient interactions and allow for the judicious choice of excipients when designing formulations containing moisture-sensitive drugs.

Unveiling the Influence of Glutathione in Suppressing the Conversion of Aspirin to Salicylic Acid: A Fluorescence and DFT Study.

Aspirin is a commonly used nonsteroidal anti-inflammatory drug, associated with many adverse effects. The adverse effects of aspirin such as tinnitus, Reye's syndrome and gastrointestinal bleeding are caused due to conversion of aspirin into its active metabolite salicylic acid after oral intake. Glutathione is a naturally occurring antioxidant produced by the liver and nerve cells in the central nervous system. It helps to metabolize toxins, break down free radicles, and support immune function. This study aims to investigate and explore the possibility of inhibiting aspirin to salicylic acid conversion in presence of glutathione at a molecular level using spectroscopic techniques such as UV-Visible absorption, time-Resolved and time-dependent fluorescence and theoretical DFT/ TD-DFT calculations. The results of steady state fluorescence spectroscopy and time-dependent fluorescence indicated that the aspirin to salicylic acid conversion is considerably inhibited in presence of glutathione. Further, the results presented here might have significant clinical implications for individuals with variations in glutathione level.

Vibrational spectroscopic detection and analysis of salicylic acid and aspirin binary cocrystal.

Salicylic acid is a raw material for preparing aspirin and holds an important position in medical history. Studying the crystallization of these two drugs is of great significance in improving their dissolution rate, bioavailability, and physical stability. Although various techniques have been used for structural characterization, there is still a lack of information on the collective vibrational behavior of aspirin and salicylic acid eutectic compounds. Firstly, two starting materials (salicylic acid and aspirin) were ground in a 1:1 M ratio to prepare eutectic compounds. The eutectic composition was studied using vibrational spectroscopy techniques, such as X-ray powder diffusion (XRPD), terahertz time-domain spectroscopy (THz-TDS), and Raman spectroscopy. Additionally, the structure of the aspirin and salicylic acid eutectic was simulated and optimized using density functional theory. It was found that the eutectic type II was the most consistent with the experiment, and the corresponding vibration modes of each peak were provided. These results offer a unique method for characterizing the structural composition of eutectic crystals, which can be utilized to enhance the physical and chemical properties, as well as the pharmacological activity, of specific drugs at the molecular level.

Amino Acids as Chelating Ligands for Platinum: Enhanced Stability in an Aqueous Environment Promoted by Biocompatible Molecules.

Platinum-based chemotherapeutics are a cornerstone in the treatment of many malignancies. However, their dose-limiting side effects have rooted efforts to develop new drug candidates with higher selectivity for tumor tissues and less problematic side effects. Here, we developed a cytotoxic platinum(II) complex based on Zeise's salt, containing the nonsteroidal anti-inflammatory drug acetylsalicylic acid and alanine as ligands (4). The previously developed complex (5) displayed high reactivity against sulfur-containing biomolecules; therefore, we put the focus on the optimization of the structure regarding its stability. Different amino acids were used as biocompatible chelating ligands to achieve this aim. Differences in the coordination sphere caused pronounced changes in the stability of Zeise-type precursors 1-3. Coordination with l-Ala through N in the trans position to ethylene showed the most promising results and was employed to stabilize 5. As a result, complex 4 showed improved stability and cytotoxicity, outperforming both 5 and 1.

Relative Humidity Cycling: Implications on the Stability of Moisture-Sensitive Drugs in Solid Pharmaceutical Products.

The stability of a moisture-sensitive drug in tablet formulations depends particularly on the environment's relative humidity (RH) and the products' prior exposure to moisture. This study was designed to understand drug stability in relation to the moisture interaction of the excipients, moisture history of the tablets, and RH of the environment. The stability study was performed on tablets containing acetylsalicylic acid (ASA), formulated with common pharmaceutical excipients like native maize starch, microcrystalline cellulose (MCC), partially pregelatinized maize starch (PGS), dicalcium phosphate dihydrate (DCP), lactose, and mannitol. The tablets were subjected to storage conditions with RH cycling alternating between 53% and 75%. Results were also compared to tablets stored at a constant RH of 53% or 75%. The excipients demonstrated marked differences in their interactions with moisture. They could be broadly grouped as excipients with RH-dependent moisture content (native maize starch, MCC, and PGS) and RH-independent moisture content (DCP, lactose, and mannitol). As each excipient interacted differently with moisture, degradation of ASA in the tablets depended on the excipients' ability to modulate the moisture availability for degradation. The lowest ASA degradation was observed in tablets formulated with low moisture content water-soluble excipients, such as lactose and mannitol. The impact of RH cycling on ASA stability was apparent in tablets containing native maize starch, MCC, PGS, or DCP. These findings suggested that the choice of excipients influences the effect of moisture history on drug stability. The results from studies investigating moisture interaction of excipients and drug stability are valuable to understanding the inter-relationship between excipients, moisture history, and drug stability.

From Solution Studies of Pharmaceuticals (Aspirin and Related Compounds) to the Thermodynamics of Aspirin-ß-Cyclodextrin Interaction in water and N,N-Dimethylformamide.

The solution behavior of pharmaceuticals (acetylsalicylic acid, 4-acetoxybenzoic acid and 5-acetylsalicylic acid) in water and N,N-Dimethylformamide (DMF) at 298.15 K were investigated through solubility, conductance and calorimetric measurements. Taking into account the formation of ion pairs of these pharmaceuticals in water, the solution Gibbs energies of the dissociated electrolytes in this solvent were calculated. Thus, the solution thermodynamics of these compounds in water are reported using enthalpy data obtained by calorimetry. These pharmaceuticals undergo solvation when exposed to a saturated atmosphere of DMF. As the composition of the solid is not the same as that in solution, the Gibbs energy of the solutions of these compounds could not be obtained; only enthalpy data are reported. The thermodynamics of the interaction of acetylsalicylic acid (aspirin) with ß-cyclodextrin in water and DMF is fully discussed, emphasizing the two different processes that take place in water at the two different pHs. In all cases, the favorable Gibbs energies for these processes are entropically controlled, mainly resulting from the higher dehydration/desolvation that the receptor undergoes upon interaction with the guest.

Design, synthesis and anticancer evaluation of novel Se-NSAID hybrid molecules: Identification of a Se-indomethacin analog as a potential therapeutic for breast cancer.

A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid, naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a larger panel of cancer cells and were also submitted to the DTP program of the NCI's panel of 60 cancer cell lines. Compounds 4a and 4d stood out with IC50 values below 10 µM in several cancer cells along with a selectivity index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic drug for breast cancer.

Combined royal jelly 10-hydroxydecanoic acid and aspirin has a synergistic effect against memory deficit and neuroinflammation.

Alzheimer's disease (AD), the most common form of neurodegenerative dementia among the older population, is associated with acute or chronic inflammation. As a nonsteroidal anti-inflammatory drug, aspirin has recently been widely studied in the prevention and treatment of neurodegenerative diseases. However, there is a controversy about the efficacy as well as the adverse effects of aspirin. 10-Hydroxydecanoic acid (10-HDAA) is a characteristic fatty acid found in the honey bee product royal jelly. In this study, we found that 10-HDAA attenuated the activation of the NF-κB pathway, then targeted Ptgs-1/2, the well-known target of aspirin. Hence, combined therapy of 10-HDAA and aspirin was conducted. In vitro assays suggested that this combinatory group alleviated LPS-induced inflammation in BV-2 cells, as assessed by the downregulation of nitric oxide, COX-2, and IL-6 compared to 10-HDAA or aspirin treatment alone. In vivo assays showed that the combined treatment synergistically inhibited the overactivation of glial cells and decreased the levels of pro-inflammatory mediators. Moreover, 10-HDAA alleviated the adverse effects of aspirin on gastrointestinal injuries and microbiota dysbiosis. The Morris water maze test indicated that neither 10-HDAA nor aspirin effectively improved LPS-induced memory dysfunction, but the combined therapy showed synergistic effects. Altogether, our findings support 10-HDAA and aspirin combinatory therapy as the basis for future therapeutics for AD and other neuroinflammation-related diseases with minimal adverse effects.

Development and Validation of a Novel HPLC Method to Analyse Metabolic Reaction Products Catalysed by the CYP3A2 Isoform: In Vitro Inhibition of CYP3A2 Enzyme Activity by Aspirin (Drugs Often Used Together in COVID-19 Treatment).

Aspirin (also known as acetylsalicylic acid) is a drug intended to treat fever, pain, or inflammation. Treatment of moderate to severe cases of COVID-19 using aspirin along with dexamethasone has gained major attention globally in recent times. Thus, the purpose of this study was to use High-Performance Liquid Chromatography (HPLC) to evaluate the in vitro inhibition of CYP3A2 enzyme activity using aspirin in rat liver microsomes (RLMs). In this study, an efficient and sensitive HPLC method was developed using a reversed phase C18 column (X Bridge 4.6 mm × 150 mm, 3.5 µm) at 243 nm using acetonitrile and water (70:30 v/v). The linearity (r2 > 0.999), precision (<15%), accuracy and recovery (80-120%), limit of detection (5.60 µM and 0.06 µM), limit of quantification (16.98 µM and 0.19 µM), and stability of the newly developed method were validated for dexamethasone and 6ß-hydroxydexamethasone, respectively, following International Conference on Harmonization (ICH) guidelines. This method was applied in vitro to measure CYP3A2 activity. The results showed that aspirin competitively inhibits 6ß-hydroxylation (CYP3A2 activity) with an inhibition constant (Ki) = 95.46 µM and the concentration of the inhibitor causing 50% inhibition of original enzyme activity (IC50) = 190.92 µM. This indicated that there is a minimal risk of toxicity when dexamethasone and aspirin are co-administrated and a very low risk of toxicity and drug interaction with drugs that are a substrate for CYP3A2 in healthcare settings.

New Insights into the Crystallographic Disorder in the Polymorphic Forms of Aspirin from Low-Frequency Vibrational Analysis.

Terahertz time-domain spectroscopy (THz-TDS) is applied to two polymorphs of acetylsalicylic acid (aspirin), and the experimental spectra are compared to lattice dynamical calculations using high accuracy density functional theory. The calculations confirm that forms I and II have very close energetic and thermodynamic properties and also that they show similar spectral features in the far-infrared region, reflecting the high degree of similarity in their crystal structures. Unique vibrational modes are identified for each polymorph which allow them to be distinguished using THz-TDS measurements. The observation of spectral features attributable to both polymorphic forms in a single sample, however, provides further evidence to support the hypothesis that crystalline aspirin typically comprises intergrown domains of forms I and II. Differences observed in the baseline of the measured THz-TDS spectra indicate a greater degree of structural disorder in the samples of form II. Calculated Gibbs free-energy curves show a turning point at 75 K, inferring that form II is expected to be more stable than form I above this temperature as a result of its greater vibrational entropy. The calculations do not account for any differences in configurational entropy that may arise from expected structural defects. Further computational work on these structures, such as ab initio molecular dynamics, would be very useful to further explore this perspective. Here, aspirin is a model system to show how the additional insight from the low-frequency vibrational information complements the structural data and allows for quantitative thermodynamic information of pharmaceutical polymorphs to be extracted. The methodology is directly applicable to other polymorphic systems.

Activated Carbon Fiber Cloth/Biomimetic Apatite: A Dual Drug Delivery System.

A biomaterial that is both bioactive and capable of controlled drug release is highly attractive for bone regeneration. In previous works, we demonstrated the possibility of combining activated carbon fiber cloth (ACC) and biomimetic apatite (such as calcium-deficient hydroxyapatite (CDA)) to develop an efficient material for bone regeneration. The aim to use the adsorption properties of an activated carbon/biomimetic apatite composite to synthetize a biomaterial to be used as a controlled drug release system after implantation. The adsorption and desorption of tetracycline and aspirin were first investigated in the ACC and CDA components and then on ACC/CDA composite. The results showed that drug adsorption and release are dependent on the adsorbent material and the drug polarity/hydrophilicity, leading to two distinct modes of drug adsorption and release. Consequently, a double adsorption approach was successfully performed, leading to a multifunctional and innovative ACC-aspirin/CDA-tetracycline implantable biomaterial. In a second step, in vitro tests emphasized a better affinity of the drug (tetracycline or aspirin)-loaded ACC/CDA materials towards human primary osteoblast viability and proliferation. Then, in vivo experiments on a large cortical bone defect in rats was carried out to test biocompatibility and bone regeneration ability. Data clearly highlighted a significant acceleration of bone reconstruction in the presence of the ACC/CDA patch. The ability of the aspirin-loaded ACC/CDA material to release the drug in situ for improving bone healing was also underlined, as a proof of concept. This work highlights the possibility of bone patches with controlled (multi)drug release features being used for bone tissue repair.

Synthesis of aspirin-curcumin mimic conjugates of potential antitumor and anti-SARS-CoV-2 properties.

Series of piperidone-salicylate conjugates were synthesized through the reaction of 3E,5E-bis(arylidene)-4-piperidones with the appropriate acid chloride of acetylsalicylate in the presence of triethylamine. All the synthesized conjugates reveal antiproliferative properties against A431 (squamous skin) cancer cell line with potency higher than that of 5-fluorouracil. Many of the synthesized agents also exhibit promising antiproliferative properties against HCT116 (colon) cancer cell line, of which 5o and 5c are the most effective with 12.9, 9.8 folds potency compared with Sunitinib. Promising activity is also shown against MCF7 (breast) cancer cell line with 1.19, 1.12 folds relative to 5-fluorouracil. PI-flow cytometry of compound 5c supports the arrest of cell cycle at G1-phase. However, compound 5o and Sunitinib arrest the cell cycle at S-phase. The synthesized conjugates can be considered as multi-targeted tyrosine kinase inhibitors due to the promising properties against VEGFR-2 and EGFR in MCF7 and HCT116. CDOCKER studies support the EGFR inhibitory properties. Compounds 5p and 5i possessing thienylidene heterocycle are anti-SARS-CoV-2 with high therapeutic indices. Many of the synthesized agents show enhanced COX-1/2 properties than aspirin with better selectivity index towards COX-2 relative to COX-1. The possible applicability of the potent candidates discovered as antitumor and anti-SARS-CoV-2 is supported by the safe profile against normal (non-cancer, RPE1 and VERO-E6) cells.

Mechanochemical synthesis insights and solid-state characterization of quininium aspirinate, a glass-forming drug-drug salt.

Quinine (an antimalarial) and aspirin (a nonsteroidal anti-inflammatory drug) were combined into a new drug-drug salt, quininium aspirinate, C20H25N2O2+·C9H7O4-, by liquid-assisted grinding using stoichiometric amounts of the reactants in a 1:1 molar ratio, and water, EtOH, toluene, or heptane as additives. A tetrahydrofuran (THF) solution of the mechanochemical product prepared using EtOH as additive led to a single crystal of the same material obtained by mechanochemistry, which was used for crystal structure determination at 100 K. Powder X-ray diffraction ruled out crystallographic phase transitions in the 100-295 K interval. Neat mechanical treatment (in a mortar and pestle, or in a ball mill at 20 or 30 Hz milling frequencies) gave rise to an amorphous phase, as shown by powder X-ray diffraction; however, FT-IR spectroscopy unambiguously indicates that a mechanochemical reaction has occurred. Neat milling the reactants at 10 and 15 Hz led to incomplete reactions. Thermogravimetry and differential scanning calorimetry indicate that the amorphous and crystalline mechanochemical products form glasses/supercooled liquids before melting, and do not recrystallize upon cooling. However, the amorphous material obtained by neat grinding crystallizes upon storage into the salt reported. The mechanochemical synthesis, crystal structure analysis, Hirshfeld surfaces, powder X-ray diffraction, thermogravimetry, differential scanning calorimetry, FT-IR spectroscopy, and aqueous solubility of quininium aspirinate are herein reported.

Serum Albumin: A Multifaced Enzyme.

Human serum albumin (HSA) is the most abundant protein in plasma, contributing actively to oncotic pressure maintenance and fluid distribution between body compartments. HSA acts as the main carrier of fatty acids, recognizes metal ions, affects pharmacokinetics of many drugs, provides the metabolic modification of some ligands, renders potential toxins harmless, accounts for most of the anti-oxidant capacity of human plasma, and displays esterase, enolase, glucuronidase, and peroxidase (pseudo)-enzymatic activities. HSA-based catalysis is physiologically relevant, affecting the metabolism of endogenous and exogenous compounds including proteins, lipids, cholesterol, reactive oxygen species (ROS), and drugs. Catalytic properties of HSA are modulated by allosteric effectors, competitive inhibitors, chemical modifications, pathological conditions, and aging. HSA displays anti-oxidant properties and is critical for plasma detoxification from toxic agents and for pro-drugs activation. The enzymatic properties of HSA can be also exploited by chemical industries as a scaffold to produce libraries of catalysts with improved proficiency and stereoselectivity for water decontamination from poisonous agents and environmental contaminants, in the so called "green chemistry" field. Here, an overview of the intrinsic and metal dependent (pseudo-)enzymatic properties of HSA is reported to highlight the roles played by this multifaced protein.

Dual-drug delivery system based on the hydrogels of alginate and sodium carboxymethyl cellulose for colorectal cancer treatment.

To improve the efficacy of chemotherapy and relieve the pain associated with colorectal cancer, a dual-drug delivery system (DDDS) is proposed. In this system, methotrexate (MTX) loaded CaCO3 (CaCO3/MTX) and aspirin (Asp) are co-entrapped in the hydrogels of alginate (Alg) and sodium carboxymethyl cellulose (CMC) crosslinked with Ca2+. The hydrogels can protect the anti-cancer drug of MTX from being absorbed in stomach and small intestine and ensure their efficacy at the target site of colorectum. More importantly, dual pH-responsive drug delivery can be achieved by the DDDS. Because the pH varies at small intestine and colorectum of human body, dual pH-responsive delivery of Asp and MTX can be achieved at the two organs, respectively, in response to ambient pH. These finding are of significant importance for medical science and pharmaceutics.

Mechanically Triggered Hybridization Chain Reaction.

Cells transmit piconewton forces to receptors to mediate processes such as migration and immune recognition. A major challenge in quantifying such forces is the sparsity of cell mechanical events. Accordingly, molecular tension is typically quantified with high resolution fluorescence microscopy, which hinders widespread adoption and application. Here, we report a mechanically triggered hybridization chain reaction (mechano-HCR) that allows chemical amplification of mechanical events. The amplification is triggered when a cell receptor mechanically denatures a duplex revealing a cryptic initiator to activate the HCR reaction in situ. Importantly, mechano-HCR enables direct readout of pN forces using a plate reader. We leverage this capability and measured mechano-IC50 for aspirin, Y-27632, and eptifibatide. Given that cell mechanical phenotypes are of clinical importance, mechano-HCR may offer a convenient route for drug discovery, personalized medicine, and disease diagnosis.

Synthesis of casein-γ-polyglutamic acid hydrogels by microbial transglutaminase-mediated gelation for controlled release of drugs.

Casein-based hydrogels were reported as biodegradability, biocompatibility, and non-toxic materials that had potential in drug delivery. At present, we prepared two kinds of casein/γ-PGA hybrid hydrogels, 1/5 and 1/9, based on the ratio of γ-PGA to casein. The hydrogels were crosslinked by microbial transglutaminase (MTG), the physicochemical properties of the casein/γ-PGA hydrogels were investigated by scanning electron microscopy (SEM) observation, differential scanning calorimetry (DSC) analysis, texture analysis, swelling ratio test, and stability test. The hydrogels showed a well-interconnected sparse and porous structure. The 1/5 casein/γ-PGA hydrogel was much stable, hard, and cohesive than the 1/9 casein/γ-PGA hydrogel, and the 1/5 casein/γ-PGA hydrogel showed a higher swelling ratio and lower degradation rate. To investigate in vitro release behavior, we chose the hydrophilic vitamin B12 and hydrophobic aspirin as the model drugs incorporated into the casein/γ-PGA hydrogels. The 1/5 casein/γ-PGA hydrogel exhibited a good drug release behavior.

Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes with Gemcitabine Cytotoxicity.

Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal overall survival benefits and cause severe adverse effects. We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an induction of G1 cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-κB) complex and the top functions as cell cycle, cell death, and survival without inducing the DNA damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha (TNF-α)-stimulated NF-κB nuclear translocation, DNA binding activity, and degradation of cytosolic inhibitor of κB (IκB) protein. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy.