Human Liver Cancer Cell Lines Research Articles

Evaluation of the anti-inflammatory, antioxidant, and cytotoxic potential of Cardamine amara L. (Brassicaceae): A comprehensive biochemical, toxicological, and in silico computational study.

Introduction: Cardamine amara L. (Brassicaceae) is an important edible plant with ethnomedicinal significance. This study aimed at evaluating the phytochemical composition, anti-inflammatory, antioxidant and cytotoxicity aspects of the hydro-alcoholic extract of C. amara (HAECA). Methods: The phytochemical composition was evaluated through total phenolic contents (TPC), total flavonoid contents (TFC) determination and UPLC-QTOF-MS profiling. Anti-inflammatory evaluation of HAECA was carried out through the carrageenan induced paw edema model. Four in vitro methods were applied in the antioxidant evaluation of HAECA. MTT assay was used to investigate the toxicity profile of the species against human normal liver cells (HL7702), human liver cancer cell lines (HepG2) and human breast cancer cell lines (MCF-7). Three major compounds (Gentisic acid, skullcapflavone and conidendrine) identified in UPLC-Q-TOF-MS analysis were selected for in silico study against cyclooxygenase (COX-I and COX-II). Results and Discussion: The findings revealed that HAECA is rich in TPC (39.32 ± 2.3mg GAE/g DE) and TFC (17.26 ± 0.8mg RE/g DE). A total of 21 secondary metabolites were tentatively identified in UPLC-Q-TOF-MS analysis. In the MTT cytotoxicity assay, the extract showed low toxicity against normal cell lines, while significant anticancer activity was observed against human liver and breast cancer cells. The carrageenan induced inflammation was inhibited by HAECA in a dose dependent manner and showed a marked alleviation in the levels of oxidative stress (catalase, SOD, GSH) and inflammatory markers (TNF-α, IL-1β). Similarly, HAECA showed maximum antioxidant activity through the Cupric reducing power antioxidant capacity (CUPRAC) assay (31.21 ± 0.3mg TE/g DE). The in silico study revealed a significant molecular docking score of the three studied compounds against COX-I and COX-I. Conclusively the current study encourages the use of C. amara as a novel polyphenolic rich source with anti-inflammatory and antioxidant potential and warrants further investigations on its toxicity profile.

Anticancer, Antidiabetic and Antimicrobial Activity Study of Biologically Active Vanadium(IV) Mixed Ligand Complexes

Introduction: Cancer and diabetes are proving to be lethal to human society and have attracted attention of researchers around the world. Synthesis of mixed ligand complexes is a challeng-ing area owing to their potential applications as drugs against various diseases. Methods: Synthesis and biological evaluation of mixed ligand complexes of Vanadium(IV) with hetero-cyclic bidentate molecule 8-hydroxyquinoline as primary ligand and L-Amino acids such as L-cysteine, L-alanine, L-phenylalanine, L-threonine and L-serine as secondary ligands is reported here. All the complexes were characterized using IR, electronic, Mass, TGA/DTA method, powder XRD analysis, molar conductance and magnetic susceptibility measurements and were screened for their biological activities. Results: The synthesized mixed ligand complexes were screened for their antibacterial activity against E. coli and antifungal activity against C. albicans. They were also evaluated for in vitro antidibetic ac-tivity, anticancer activity against HepG2 (human liver cancer cell line) by MTT assay. Conclusion: The synthesized mixed ligand complexes were thermally stable, paramagnetic, non-electrolytic in nature and proposed to have square pyramidal geometry. They also exhibited potential as antibacterial, anticancer and antidibetic agents.

The Combination Sorafenib-raloxifene-loratadine as a Novel Potential Therapeutic Approach Against Human Liver Cancer.

Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect. The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively. In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations. The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.

Synthesis, characterization, and antiproliferative evaluation of novel sorafenib analogs for the treatment of hepatocellular carcinoma.

Cancer is a disease triggered by an uncontrolled proliferation of a cluster of cells, typically originating from a single cell. Sorafenib, a widely utilized pharmaceutical, has limitations in clinical use due to pharmacokinetic challenges and the development of resistance mechanisms. This investigation aimed to synthesize new sorafenib analogs and evaluated their activity against HepG2 cell lines, specifically targeting hepatocellular carcinoma (HCC). Seven sorafenib analogs were synthesized and identified by Fourier-transform infrared spectroscopy and 1H-NMR spectra. Cytotoxicity of the analogs was assessed on the human HepG2 cancer cell line by (3-(4, 5-dimethylthazolk-2-yl)-2, 5-diphenyl tetrazolium bromide) colorimetric assay. Results revealed that among the studied compounds, 4b exhibited the most pronounced cytotoxicity against cancer cells, surpassing even the efficacy of sorafenib. This suggested that small substitutions on the NH moiety play a crucial role in the activity against the human HepG2 liver cancer cell line. These findings provide valuable insights for the development of potential anticancer-targeting HCC.

Synthesis and evaluation of biological activities of two belinostat analogs bearing fluorine at the CAP

Histone deacetylase enzymes are overexpressed in many types of hematologic malignancies (acute myelogenous leukemia, myelofibrosis, cutaneous T-cell lymphoma, and Hodgkin lymphoma) and their inhibition of HDACs could result in the inhibition of cell proliferation and induction of apoptosis. Thus, HDAC inhibitors are candidates of anticancer drug development. Belinostat is a histone deacetylase inhibitor which was approved by the US FDA in 2014 for the treatment of refractory T-cell lymphoma and solid tumor. This paper reported the synthesis of two belinostat analogues (including a firstly synthesized compound) by introducing fluorine atoms at the hydrophobic capping group (CAP) of belinostat. The resulted compounds were then tested by molecular docking analysis and in vitro evaluation of their antioxidant and anti-cancer activities. The new compound 8a displayed the highest anti-cancer efficacy against human breast (MCF-7) and liver (Hep-G2) cancer cell lines with EC50 values of 1.5‒4.0 μg/mL. Two compounds showed the antioxidant activity with an EC50 value of 8.30‒13.60 μg/mL. These results suggested that the synthesized belinostat analogs might have anti-cancer potential for further investigation.

PH and Thermoresponsive PNIPAm-co-Polyacrylamide Hydrogel for Dual Stimuli-Responsive Controlled Drug Delivery.

The therapeutic delivery system with dual stimuli-responsiveness has attracted attention for drug delivery to target sites. In this study, we used free radical polymerization to develop a temperature and pH-responsive poly(N-isopropyl acrylamide)-co-poly(acrylamide) (PNIPAM-co-PAAm). PNIPAm-co-PAAm copolymer by reacting with N-isopropyl acrylamide (NIPAm) and acrylamide (Am) monomers. In addition, the synthesized melamine-glutaraldehyde (Mela-Glu) precursor was used as a cross-linker in the production of the melamine cross-linked PNIPAm-co-PAAm copolymer hydrogel (PNIPAm-co-PAAm-Mela HG) system. The temperature-responsive phase transition characteristics of the resulting PNIPAM-co-PAAm-Mela HG systems were determined. Furthermore, the pH-responsive drug release efficiency of curcumin was investigated under various pH and temperature circumstances. Under the combined pH and temperature stimuli (pH 5.0/45 °C), the PNIPAm-co-PAAm-Mela HG demonstrated substantial drug loading (74%), and nearly complete release of the loaded drug was accomplished in 8 h. Furthermore, the cytocompatibility of the PNIPAm-co-PAAm-Mela HG was evaluated on a human liver cancer cell line (HepG2), and the findings demonstrated that the prepared PNIPAm-co-PAAm-Mela HG is biocompatible. As a result, the PNIPAm-co-PAAm-Mela HG system might be used for both pH and temperature-stimuli-responsive drug delivery.

Synthesis of Few New Carrier Polymers Derived from 2-hydrazinylbenzo[d]thiazole

2-hydrazinylbenzo[d]thiazole compound [1] is produced from reaction of 2-mercapto-benzothiazole with hydrazine hydride in ethanol. Compound [1] reacted with maleic anhydride in DMF to produce (Z)-4-(2-(benzo[d] thiazol-2yl) hydrazinyl)-4-oxobut-2-enoic acid [compound (2)]. While the treatment of compound [2] with the ammonium persulfate (NH4)2S2O8 (as the initiator) in order to produce compound [3], then compound [3] reacted with thionyl chloride in benzene to produce compound [4], finally compound [4] reaction with various drugs: cephalexin, amoxicillin, sulfamethizole, elecoxib obtained polymers [5–8]. The structure of synthesized compounds identified by spectral data: fourier transform infrared (FTIR) and proton nuclear magnetic resonance (1HNMR) spectroscopy. The polymers [5–8] have been screened for their antibacterial activities against Staphylococcus aureus (G+), Escherichia coli (G-) and compared with the drug (amoxicillin). The anticancer activity (Hep G2 (human liver cancer cell line) of some prepared polymers were also studied.

Optimized pressurized hot water extraction, HPLC/LC-MS characterization, and bioactivity of Tetrapleura tetraptera L. dry fruit polyphenols.

Despite the global preference for green extraction methods in the recovery of plant bioactives, Tetrapleura tetraptera fruit polyphenols (TTP) are yet to receive considerable attention. For the first time, pressurized hot water extraction (PHWE) of TTP was optimized for total phenol content (TPC) and antioxidant activity (AA) using the Box Behnken design of response surface methodology. Predictor variables were time, temperature, and liquid-to-solid ratio. An optimum solution with a desirability of 0.805 was selected and parameters were 43min, 220°C, and 60ml g-1 liquid-to-solid ratio, yielding TPC of 8.92mg gallic acid equivalent per gram of sample on dry weight basis (GAE g-1 dw-1 ) and AA of 70.35%. Purified, optimized TTP were characterized and quantified using HPLC/LC-MS. PHWE mainly extracted rutin (379.04µg g-1 ), cyanidin-3-O-glucoside (chloride) (299.55µg g-1 ), naringenin 7-O-glucoside (240.11µg g-1 ), p-coumaric acid (177.28µg g-1 ), isorientin (150.43µg g-1 ), and gallic acid (118.06µg g-1 ) whereas cyanidin-3-O-glucoside (chloride) (83.27µg g-1 ), protocatechuic acid (61.37µg g-1 ), rutin (28.03µg g-1 ), and gallic acid (22.62µg g-1 ) were mainly extracted by hot water extraction, which was a control. PHWE-obtained TTP showed higher cellular antioxidant activity, cytotoxicity in human liver cancer cell lines (HepG2), and antimicrobial property against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis than control. The potential mechanisms underlying the biological activities of some of the major polyphenols extracted were briefly discussed. Considering the wide use of the T. tetraptera (TT) fruit in Africa in foods and medicine, the use of more efficient green extraction methods such as PHWE is recommended. PRACTICAL APPLICATION: This study serves as a baseline for optimizing pressurized hot water extraction, purification, identification, and quantification of Tetrapleura tetraptera polyphenols (TTP) and their biological activities, being the first of its kind. The varied biological effects shown can be exploited further for applications of TTP as nutraceutical agents and preservatives in foods in different forms. Also, the high amounts of gallic acid and other phenolic acids and flavonoids confirmed in this study make TTP good candidates for the development of metal-phenol network nanoparticles to enhance adequate solubility and distribution in food systems in light of the above proposed applications.

Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1,2,4-triazole.

Novel azomethines derived from acefylline tethered triazole hybrids (7a-k) have been synthesized and evaluated against human liver cancer cell line (Hep G2) using MTT assay. The synthesized series of azomethines exhibited promising efficacy against liver cancer cell line. Screening of the synthesized series identified compound 7d with the least cell viability value (11.71 ± 0.39%) as the most potent anticancer agent in contrast to the reference drug acefylline (cell viability = 80 ± 3.87%). In this study, the potentials of the novel agents (7a-k) to inhibit liver cancer proteins were assessed. Subsequently, the structure-activity relationship of the potential drug candidates was assessed via ADME/T molecular screening. The cytotoxic potential of these derivatives was also investigated by hemolysis and thrombolysis. Their hemolytic and thrombolytic studies showed that all of these drugs had very low cytotoxicity and moderate clot lysis activity. Compound 7g (0.26% hemolysis) and 7k (52.1% clot lysis) were the least toxic and moderate thrombolytic agents respectively.

Role of AHR, NF-kB and CYP1A1 crosstalk with the X protein of Hepatitis B virus in hepatocellular carcinoma cells

In this study, it was aimed to elucidate the interaction between aryl hydrocarbon receptor (AHR), nuclear factor-kappa B (NF-kB), and cytochrome P4501A1 (CYP1A1) with hepatitis B virus X protein (HBX) in a human liver cancer cell line (HepG2) transfected with HBX. First, AHR, NF-kB, and CYP1A1 genes were cloned into the appropriate region of the CheckMate mammalian two-hybrid recipient plasmids using a flexi vector system. Renilla and firefly luciferases were quantified using the dual-luciferase reporter assay system to measure the interactions. Secondly, transient transfections of CYP1A1 and NF-kB (RelA) were performed into HBX–positive and HBX–negative HepG2 cells. The mRNA expression of CYP1A1 and NF-kB genes were confirmed with RT-PCR, and cell viability was measured by WST-1. Further verification was assessed by measuring the activity and protein level of CYP1A1. Additionally, CYP1A1/HBX protein–protein interactions were performed with co-immunoprecipitation, which demonstrated no interaction. These results have clearly shown that the NF-kB and AHR genes interact with HBX without involving CYP1A1 and HBX protein–protein interactions. The present study confirms that AHR and NF-kB interaction plays a role in the HBV mechanism mediated via HBX and coordinating the carcinogenic or inflammatory responses; still, the CYP1A1 gene has no effect on this interaction.

A New abeo-Icetexane-Type Diterpenoid from the Stem Barks of Taxus wallichiana.

From a CH2 Cl2 -soluble fraction of the stem barks of Taxus wallichiana, one new abeo-icetexane-type diterpenoid, taxamairin I (1), was isolated. Its absolute configuration was elucidated based on spectroscopic interpretation and time-dependent density functional theory (TD-DFT) calculation of optical rotation. In addition, the plausible biosynthesis pathway for the formation of the new abeo-icetexane-type diterpenoid was proposed. Taxamairin I (1), at a concentration of 100 μM, did not show cytotoxicity against Hep3B human liver cancer cell lines.

Dry Grinding Synthesis and Docking Study of Cyclopentanone-Sulfur Containing Compounds with Anti-Proliferative Activity for HepG-2 and A-549 Cancer Cell Lines.

The dry grinding method is a green technique for efficient organic synthesis with numerous advantages, such as mild reaction conditions, environmental acceptability, simple segregation, and refinement, as well as elevated selectivity and efficiency. The aim of the present work is to design and synthesize cyclopentylidene-hydrazino)- thiazole derivatives using dry grinding conditions to investigate their antitumor activity against two cell lines, namely, HepG-2 and A-549. In this context, we synthesized a series of thiazole incorporated cyclopentane through hydrazone- group and 2-cyclopentylidenehydrazine-1-carbimidic-2-ethoxy-N-aryl-2-oxoacetohydrazonic thioanhydride under dry grinding within minutes and excellent to good yield. All spectral data confirmed the proposed structures. In addition to antitumor activity investigations against the two kinds of cancer cells, molecular docking studies were conducted using Macrophage Migration Inhibitory Factor (Pdb: 4k9g) and Lysozyme C (Pdb: 2f4a), the overexpressed proteins in the human liver cancer cell (HepG-2) and lung cancer cell lines (A-549), respectively. Two derivatives, 9b, and 9d, showed the highest antitumor activity against the two cell lines HepG-2 and A-549. Also, docking results revealed a high energy score ranging from -7.1590 to -5.9364 Kcal/mol with Macrophage Migration Inhibitory Factor (Pdb: 4k9g), more than that the energy score = -4.118 Kcal/mol of co-crystallized ligand. Moreover, the tested derivatives showed energy score varies from -6.0802 to -4.5503 Kcal/mol against Lysozyme C (Pdb: 2f4a).

Comparative study of the chemical composition and anti-proliferative activities of the aerial parts and roots of Apium graveolens L. (celery) and their biogenic nanoparticles

• The aerial parts and roots of celery showed potent antiproliferative effects against human tumor cells. • The secondary metabolites of both organs were explored by HPLC‒HESI‒HRMS metabolomics. • Potent cytotoxic nanoparticles were green synthesized from the extracts of both celery parts. • Molecular docking of the identified metabolites revealed their possible inhibition of GAK. • Celery and its biogenic nanoparticles are therefore relevant sources to functional food and drug development. Apiaceae plants are multipurpose folk remedies and bioactive foods that show a remarkable ability to biosynthesize a large number of secondary metabolites with antitumor and chemopreventive potential. Among the various members of the Apiaceae, celery ( Apium graveolens L.) has long been used as a popular edible and medicinal plant owing to its plentiful health benefits and nutraceutical properties; however, the anticancer potential of this important species has been seldom studied, mostly focusing on its seeds. Therefore, this work was designed to delve into the chemical composition and anti-proliferative potential of the total ethanolic extracts of the aerial parts (TEEAGA) and roots (TEEAGR) of A. graveolens var. dulce (Mill.) Pers. as well as their green synthesized silver nanoparticles (AgNPs). In general, both TEEAGA and TEEAGR exhibited moderate to potent inhibitory activities against human liver (HepG-2), colon (Caco-2), and breast (MCF-7) cancer cell lines, with interesting IC 50 profiles [(41.37 ± 0.12, 27.65 ± 0.27, and 9.48 ± 0.04 μg/mL) and (11.58 ± 0.02, 7.13 ± 0.03, and 6.58 ± 0.02 μg/mL), respectively] as compared with doxorubicin, while more pronounced anti-proliferative effects were observed for their biogenic AgNPs, which showed IC 50 values ranging between 25.41 ± 0.16 and 1.37 ± 0.03 μg/mL. Moreover, HPLC‒HESI‒HRMS-based metabolomics analysis of both extracts showed the presence of a varied group of secondary metabolites, including flavonoids, phenylpropanoids, phthalides, coumarins, and sesquiterpenes that further displayed moderate to promising binding affinities to the active site of cyclin G-associated kinase (GAK), particularly graveobioside A, graveobioside B, and celeroside C, suggesting their possible contribution as GAK modulators to the anti-proliferative potential of celery. These findings can help broaden future research on the utilization of different parts of celery and their NPs as functional foods and medicines in cancer chemoprevention and therapy.

FDI-6, a FOXM1 inhibitor, activates the aryl hydrocarbon receptor and suppresses tumorsphere formation

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by environmental contaminants such as dioxins and polycyclic aromatic hydrocarbons. Following ligand binding, AhR binds to xenobiotic responsive elements and modulates the transcription of AhR target genes. Multiple studies have shown that AhR plays important roles in a range of cancer cells and is attracting attention as a therapeutic target for cancer treatment. We have previously reported that AhR agonists inhibit tumorsphere formation in an AhR-dependent manner in the MCF-7 breast cancer cell line. In the present study, we found that FDI-6, an inhibitor of the transcription factor Forkhead Box M1 (FOXM1) induced the mRNA expression of AhR target genes, nuclear translocation of AhR, and transcriptional activity of AhR. In addition, FDI-6 dose-dependently reduced the mRNA expression of FOXM1-regulated genes in AhR-expressing MCF-7 cells, although not in AhR-deficient MCF-7 cells. Furthermore, FDI-6 was found to suppress tumorsphere formation via the AhR in MCF-7 cells and HepG2 human liver cancer cell line. On the basis of the findings of this study, we show that FDI-6, a FOXM1 inhibitor, functions as an AhR agonist, and suppresses tumorsphere formation via the AhR.

Molecular Docking Studies on Methanolic Propolis Extracts Collected from Different Regions in Saudi Arabia as a Potential Inhibitor of Topoisomerase IIβ

Propolis is a sticky substance made by honeybees from various plant parts that is rich in biologically active substances such as flavonoids, phenolic acids, and phenolics and has a wide range of applications in the food, cosmetics, and pharmaceutical industries. The current study focused on the isolation of honeybee propolis samples from three different locations in Saudi Arabia: Al Hada, Baljurashi, and Rawdat Khuraim, and the evaluation of their anti-cancer effect against human liver cancer cell lines (HeP-G2) and human breast cancer cell lines (MCF-7). Five chemical compounds present in the methanolic extract of propolis honeybee were detected by HPLC. Furthermore, molecular modeling studies were conducted to explain the mechanism of anti-cancer activity exerted by the active compounds. The propolis samples collected from the three isolation sites had anti-cancer activity against MCF-7 and HeP-G2. Samples collected from the Rawdat Khuraim site showed the highest inhibitory activity reaching 81.5% and 83.2% against MCF-7 and HeP-G2, respectively. HPLC detected four main active compounds from propolis samples: pinobanksin, pinocembrin, galangin, and xanthomicrol. The molecular docking technique showed that galangin and pinocembrin had higher anti-cancer activity than xanthomicrol and pinobanksin as the binding affinity of galangin and pinocembrin with the active sites of the topoisomerase IIβ enzyme was much greater.

Antiproliferative and apoptosis-inducing effects of aqueous extracts from Ecklonia maxima and Ulva rigida on HepG2 cells.

This study examined the antiproliferative and apoptotic-inducing effects of Ecklonia maxima (KP) and Ulva rigida (URL) extracts in the human liver cancer (HepG2) cell line model. HepG2 cells were cultured and grown in an incubator (5% CO2 ) at 37°C. Cell viability was determined, while the effect of the extracts on apoptosis, ROS production, mitochondria membrane potential, and antioxidant enzymes were also assessed. KP and URL induced cytotoxic effects on HepG2 cells at the concentrations tested (0-1000 μg/ml). The morphological characteristics of the cells after treatment with KP and URL revealed cell shrinkage of the nucleus, cell injury, and damage compared to the control. The fluorescent micrographs from the apoptotic assay revealed induction of apoptosis and necrosis in HepG2 cells after treatment with KP and URL (200 and 400 μg/ml). The extracts also induced ROS production and reduced mitochondria membrane potential in HepG2 cells. The apoptotic-inducing effects, activation of ROS generation, and disruption of antioxidant enzymes are associated with the cytotoxic effects of the seaweed extracts. KP and URL showed good anticancer properties and could be explored as a good source of nutraceuticals, food additives, and dietary supplements to prevent uncontrolled proliferation of HepG2 cells. PRACTICAL APPLICATIONS: Seaweeds are reservoirs of nutrients and naturally occurring biologically active compounds, including sterols, phlorotannins, and polyunsaturated fatty acids. Due to the presence of these compounds, they are used as emulsifying agents, nutraceuticals, and additives in functional foods. Evidence suggests that seaweed bioactives may inhibit uncontrolled cell proliferation and induce apoptosis in cancer cells. Hence, exploring the antiproliferative and apoptotic-inducing effects of Ecklonia maxima and Ulva rigida will provide insights into their anticancer potentials as functional foods and nutraceuticals.

Network Pharmacological Analysis of the Red Sea Sponge Hyrtios erectus Extract to Reveal Anticancer Efficacy of Corresponding Loaded Niosomes.

In this study, the LC-HRMS-assisted chemical profiling of Hyrtios erectus sponge led to the annotation of eleven major compounds (1–11). H. erectus-derived crude extract (HE) was tested in vitro for its antiproliferative activity against three human cancer cell lines, Hep-G2 (human liver cancer cell line), MCF-7 (breast cancer cell line), and Caco-2 (colon cancer cell line), before and after encapsulation within niosomes. Hyrtios erectus extract showed moderate in vitro antiproliferative activities towards the studied cell lines with IC50 values 18.5 ± 0.08, 15.2 ± 0.11, and 13.4 ± 0.12, respectively. The formulated extract-containing niosomes (size 142.3 ± 10.3 nm, PDI 0.279, and zeta potential 22.8 ± 1.6) increased the in vitro antiproliferative activity of the entrapped extract significantly (IC50 8.5 ± 0.04, 4.1 ± 0.07, and 3.4 ± 0.05, respectively). A subsequent computational chemical study was performed to build a sponge–metabolite–targets–cancer diseases network, by focusing on targets that possess anticancer activity toward the three cancer types: breast, colon, and liver. Pubchem, BindingDB, and DisGenet databases were used to build the network. Shinygo and KEGG databases in addition to FunRich software were used for gene ontology and functional analysis. The computational analysis linked the metabolites to 200 genes among which 147 genes related to cancer and only 64 genes are intersected in the three cancer types. The study proved that the co-occurrence of compounds 1, 2, 3, 7, 8, and 10 are the most probable compounds possessing cytotoxic activity due to large number of connections to the intersected cytotoxic genes with edges range from 9-14. The targets possess the anticancer effect through Pathways in cancer, Endocrine resistance and Proteoglycans in cancer as mentioned by KEGG and ShinyGo 7.1 databases. This study introduces niosomes as a promising strategy to promote the cytotoxic potential of H. erectus extract.

α-Fetoprotein fragment synergizes with sorafenib to inhibit hepatoma cell growth and migration and promote the apoptosis.

Alpha fetoprotein (AFP) is associated with hepatocellular carcinoma (HCC) by stimulating the proliferation, metastasis and drug resistance. The application of AFP fragments to inhibit the malignant behaviours induced by AFP is a new strategy for the treatment of HCC. In an effort to design, screen and discover drugs, we attempted to express different human AFP fragments (AFP220-609 , AFP390-609 and AFP460-609 ) in a Bac-to-Bac system. We found that the AFP390-609 fragment was highly expressed in the system. Then, we assessed the bioactivity of the fragment in the human liver cancer cell line Bel7402, and the results indicated that the AFP fragment synergized with sorafenib to inhibit the hepatoma cell growth and migration and promote the apoptosis. This study provides a method to produce significant AFP fragments to screen AFP inhibitors for use in HCC therapy.

Alpinumisoflavone Impairs Mitochondrial Respiration via Oxidative Stress and MAPK/PI3K Regulation in Hepatocellular Carcinoma Cells.

Alpinumisoflavone is a natural prenylated isoflavonoid extracted from the raw fruit of Cudrania tricuspidata. Several studies have reported the beneficial characteristics of alpinumisoflavone, such as its antioxidant, anti-inflammation, anti-bacterial, osteoprotective, and neuroprotective effects. Alpinumisoflavone also has anti-cancer effects on thyroid, renal, and ovarian cancers, but its therapeutic effects on hepatocellular carcinoma (HCC) have not yet been demonstrated. We investigated the anti-cancer effects of alpinumisoflavone on HCC using human liver cancer cell lines, Hep3B and Huh7. Our results confirmed that alpinumisoflavone inhibited viability and regulated the MAPK/PI3K pathway in Hep3B and Huh7 cells. We also verified that alpinumisoflavone can depolarize the mitochondrial membrane potential and suppress the mitochondrial respiration in HCC cells. Moreover, we confirmed the dysregulation of the mitochondrial complexes I, III, and V involving mitochondrial oxidative phosphorylation at the mRNA level and the accumulation of calcium ions in the mitochondrial matrix. Lastly, we demonstrated that alpinumisoflavone induced mitochondria-mediated apoptosis via regulation of the Bcl-xL and BAK proteins. This study elucidates the anti-cancer effects of alpinumisoflavone on HCC.

Synthesis, Characterization, and Cytotoxicity of New Spirooxindoles Engrafted Furan Structural Motif as a Potential Anticancer Agent.

A new series of spirooxindoles based on ethylene derivatives having furan aryl moiety are reported. The new hybrids were achieved via [3 + 2] cycloaddition reaction as an economic one-step efficient approach. The final constructed spirooxindoles have four contiguous asymmetric carbon centers. The structure of 3a is exclusively confirmed using X-ray single crystal diffraction. The supramolecular structure of 3a is controlled by O···H, H···H, and C···C intermolecular contacts. It includes layered molecules interconnected weak C–H···O (2.675 Å), H···H (2.269 Å), and relatively short Cl···Br interhalogen interactions [3.4500(11)Å]. Using Hirshfeld analysis, the percentages of these intermolecular contacts are 10.6, 25.7, 6.4, and 6.2%, respectively. The spirooxindoles along with ethylene derivatives having furan aryl moiety were assessed against breast (MCF7) and liver (HepG2) cancer cell lines. The results indicated that the new chalcone 3b showed excellent activity in both cell lines (MCF7 and HepG2) with IC50 = 4.1 ± 0.10 μM/mL (MCF7) and 3.5 ± 0.07 μM/mL (HepG2) compared to staurosporine with 4.3 and 2.92 folds. Spirooxindoles 6d (IC50 = 4.3 ± 0.18 μM/mL), 6f (IC50 = 10.3 ± 0.40 μM/mL), 6i (IC50 = 10.7 ± 0.38 μM/mL), and 6j (IC50 = 4.7 ± 0.18 μM/mL) exhibited potential activity against breast adenocarcinoma, while compounds 6d (IC50 = 6.9 ± 0.23 μM/mL) and 6f (IC50 = 3.5 ± 0.11 μM/mL) were the most active hybrids against human liver cancer cell line (HepG2) compared to staurosporine [IC50 = 17.8 ± 0.50 μM/mL (MCF7) and 10.3 ± 0.23 μM/mL (HepG2)]. Molecular docking study exhibited the virtual mechanism of binding of compound 3b as a dual inhibitor of EGFR/CDK-2 proteins, and this may highlight the molecular targets for its cytotoxic activity.