HepG2 Cancer Cell Lines Research Articles

Bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer via modulating HAT1 and increasing IL-9.

Bevacizumab is a recombinant humanized monoclonal immunoglobulin (Ig) G1 antibody of VEGF, and inhibits angiogenesis and tumor growth in hepatocellular carcinoma (HCC). Ferroptosis, a new form of regulated cell death function independently of the apoptotic machinery, has been accepted as an attractive target for pharmacological intervention; the ferroptosis pathway can enhance cell immune activity of anti-PD1 immunotherapy in HCC. In this study we investigated whether and how bevacizumab regulated ferroptosis and immune activity in liver cancer. Firstly, we performed RNA-sequencing in bevacizumab-treated human liver cancer cell line HepG2 cells, and found that bevacizumab significantly altered the expression of a number of genes including VEGF, PI3K, HAT1, SLC7A11 and IL-9 in liver cancer, bevacizumab upregulated 37 ferroptosis-related drivers, and downregulated 17 ferroptosis-related suppressors in particular. We demonstrated that bevacizumab triggered ferroptosis in liver cancer cells by driving VEGF/PI3K/HAT1/SLC7A11 axis. Clinical data confirmed that the expression levels of VEGF were positively associated with those of PI3K, HAT1 and SLC7A11 in HCC tissues. Meanwhile, we found that bevacizumab enhanced immune cell activity in tumor immune-microenvironment. We identified that HAT1 up-regulated miR-143 targeting IL-9 mRNA 3'UTR in liver cancer cells; bevacizumab treatment resulted in the increase of IL-9 levels and its secretion via VEGF/PI3K/HAT1/miR-143/IL-9 axis, which led to the inhibition of tumor growth in vivo through increasing the release of IL-2 and Granzyme B from activated CD8+ T cells. We conclude that in addition to inhibiting angiogenesis, bevacizumab induces ferroptosis and enhances CD8+ T cell immune activity in liver cancer. This study provides new insight into the mechanisms by which bevacizumab synergistically modulates ferroptosis and CD8+ T cell immune activity in liver cancer.

Integrated in silico and in vitro discovery of a new anticancer thiadiazole analog targeting VEGFR-2

In this work, a new thiadiazole analogue (TDA) was designed with the intention of incorporating key features of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) inhibitors, and then was examined computationally and experimentally. In vitro (cytotoxicity on MCF-7, HepG2 and WI-38 cell lines, in vitro VEGFR-2 assay, cell cycle analysis, apoptosis assays, RT-PCR, and migration studies), in addition to in silico (molecular docking, ADMET, MD simulations and DFT studies) were conducted. Prior to synthesis, docking and ADMET studies yielded predictions indicating favorable activity and drug likeness. After synthesis, the results demonstrated promising inhibitory activity of TDA on MCF-7 and HepG2 cancer cell lines. These results were notably close to those of sorafenib. The in vitro VEGFR-2 assay revealed significant inhibition, with an IC50 value of 0.283 µM. Selectivity studies indicated a favorable safety profile, with reduced toxicity towards normal lung cells (WI-38). Cell cycle analysis of TDA revealed a significant arrest in the G0-G1 phase, compared to the control group. Apoptosis assays demonstrated a considerable increase in programmed cell death, particularly in the early stages as opposed to the control group. Additionally, there was a notable increase in the expression of the pro-apoptotic gene Bax and a downregulation of the anti-apoptotic gene Bcl2 in MCF-7 cells treated with TDA. TDA also exhibited an anti-angiogenic potential through decreasing the abilities of the MCF-7 cells to migrate and heal. Computationally, various MD simulations studies indicated stable interactions between TDA and VEGFR-2 over 200 ns on both mechanical and energetic levels. DFT studies confirmed reactivity and stability of TDA. These comprehensive findings emphasize TDA’s potential as a multi-targeted candidate for further development in cancer therapy. The promising inhibitory activity, favorable safety profile, and mechanistic insights highlight TDA as a noteworthy contender through further in vivo studies and modifications.

Discovery of new eremophilanes from the marine-derived fungus Emericellopsis maritima BC17 by culture conditions changes: evaluation of cytotoxic and antimicrobial activities

In our previous studies, the marine-derived fungus Emericellopsis maritima BC17 was found to produce new eremophilane-type sesquiterpenoids on solid media. In order to explore its potential to produce more metabolites, E. maritima BC17 was subjected to a one strain-many compounds (OSMAC) analysis leading to the discovery of three new eremophilanes (1-3) and fourteen known derivatives (4-17) in the liquid media Czapek Dox and PDB. Their structures were established by extensive analyses of the 1D and 2D NMR, and HRESIMS data, as well as ECD data for the assignment of their absolute configurations. Antitumoral and antimicrobial activities of the isolated metabolites 1, 3, 11, and 15 were investigated. PR toxin 3-deacetyl (15) exhibited cytotoxic activity against HepG2, MCF-7, A549, A2058 and Mia PaCa-2 human cancer cell lines with IC50 values ranging from 2.5 to 14.7 µM. In addition, 15 exhibited selective activity against methicillin-sensitive Staphylococcus aureus ATCC29213 at the highest concentration tested of 128 µg/mL.

Ultrasound-assisted synthesis of novel Schiff bases from 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde and their cytotoxicity, apoptosis, cell cycle, molecular docking, and ADMET profiling

With the ultimate goal of discovering new anticancer agents, this study involved the design and synthesis of fifteen novel Schiff bases 4a,b, 5, 6a–d, 7a–e, and 8–10 which contain 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole moiety. The synthetic method depended on reaction of 3-(2-oxo-2H-chromen-3-yl)-1-(4-phenylthiazol-2-yl)-1H-pyrazole-4-carboxaldehyde (3) with a series of aromatic and heteroaryl amines under ultrasound irradiation to explore the influence of aromatic and heteroaryl rings on biological activity. The chemical structures of these Schiff bases were fully elucidated using various spectral and elemental analyses. The antiproliferative activities of the Schiff bases were studied by the standard SRB method. Among the new 15 Schiff bases, derivatives 4a,b, 5, and 7b have significant cytotoxic effects against PC3, HepG2, and HCT116 cancer cell lines. These four bioactive Schiff bases significantly increased the late apoptosis of all studied tumor cells. Also, both products 4a and 4b arrested the cell cycle at the G1 phase, while both compounds 5 and 7b arrested the S and G2 phases against PC3 cells. In addition, the products 4a, 4b, 5, and 7b have promising high abilities to arrest the cell cycle at the G2 phase against HepG2 and HCT116 cells. The different substitutions on the aryl ring were the basis for the structure–activity relationship study. The molecular docking study confirmed good binding interactions of these compounds with Cyclin-dependent kinase 8 (CDK-8) receptor, while the absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction supported that these bioactive products can be promising anticancer agents.

LncRNA PAARH impacts liver cancer cell proliferation by engaging miR‑6512‑3p to target LASP1.

Long non-coding (lnc)RNAs serve a pivotal role as regulatory factors in carcinogenesis. The present study aimed to assess the involvement of the lncRNA progression and angiogenesis-associated RNA in hepatocellular carcinoma (PAARH) in liver cancer, along with the associated underlying mechanism. Through the use of reverse transcription-quantitative (RT-q)PCR, differences in the expression levels of PAARH in HepG2, HEP3B2.1.7, HCCLM3, Huh-7 and MHCC97-H liver cancer cell lines and THLE-2 epithelial cell lines were evaluated. The liver cancer cell line with the greatest, significantly different, level of expression relative to the normal liver cell line was selected for subsequent experiments. Using ENCORI database, the putative target genes of the microRNA (miR) miR-6512-3p were predicted. Cells were then transfected with lentiviruses carrying short-hairpin-PAARH to interfere with PAARH expression. Subsequently, HepG2 liver cancer cells were transfected with a miR-6512-3p mimic and an inhibitor, and the expression levels of miR-6512-3p and the LIM and SH3 domain protein 1 (LASP1) in cells were assessed using RT-qPCR analysis. Cell proliferation was subsequently evaluated using colony formation assays, and immunofluorescence and western blotting were used to assess the expression level of LASP1 in transfected cells. The binding interaction between miR-6512-3p and LASP1 was further evaluated using a dual-luciferase reporter gene assay. Liver cancer cells were found to exhibit higher expression levels of PAARH compared with normal liver cells. Following PAARH interference, the expression level of miR-6512-3p was significantly increased, whereas that of LASP1 was significantly decreased, resulting in a reduction in cell proliferation. In liver cancer cells, miR-6512-3p overexpression led to a significant reduction in the LASP1 level and reduced proliferation, whereas suppressing miR-6512-3p led to a significant increase in LASP1 levels and increased proliferation. Additionally, the inhibition of miR-6512-3p caused the states of low LASP1 expression and reduced cell proliferation to be reversed. LASP1, a recently identified target gene of miR-6512-3p, was demonstrated to be suppressed by miR-6512-3p overexpression, thereby inhibiting liver cancer cell proliferation. Taken together, the findings of the present study demonstrate that the lncRNA PAARH may enhance liver cancer cell proliferation by engaging miR-6512-3p to target LASP1.

Bioassay-guided isolation of cycloartane-type triterpenes, their cytotoxic properties and identification of potential chemical markers from Geniotrigona thoracica propolis

Phytochemical investigation through cytotoxicity bioassay-guided isolation of Geniotrigona thoracica propolis led to the identification of five cycloartane-type triterpenes, including mangiferonic acid 1, ambonic acid 2, mangiferolic acid 3, ambolic acid 4 and cycloartenol 5. Their structures were established based on detailed spectroscopic analysis and comparison with literature data. Compounds 1-5 were isolated for the first time in this species. From cytotoxicity MTT assay, compound 3 inhibited the growth of breast (MCF-7) and hepatocellular carcinoma (HepG2) cancer cell lines with IC50 of 5.08 and 4.82 µg/mL, respectively. Cytotoxicity of compounds 1-5 were reported for the first time against HepG2 cancer cell lines. Compounds 1-4 were suggested to serve as main and/or analytical markers for G. thoracica propolis based on HPLC analysis. To our knowledge, this is the first report on the isolation of bioactive constituents and identification of chemical markers for G. thoracica propolis.

Molecular interactions between metformin and D-limonene inhibit proliferation and promote apoptosis in breast and liver cancer cells

BackgroundCancer is a fatal disease that severely affects humans. Designing new anticancer strategies and understanding the mechanism of action of anticancer agents is imperative.Hypothesis/PurposeIn this study, we evaluated the utility of metformin and D-limonene, alone or in combination, as potential anticancer therapeutics using the human liver and breast cancer cell lines HepG2 and MCF-7.Study designAn integrated systems pharmacology approach is presented for illustrating the molecular interactions between metformin and D-limonene.MethodsWe applied a systems-based analysis to introduce a drug–target–pathway network that clarifies different mechanisms of treatment. The combination treatment of metformin and D-limonene induced apoptosis in both cell lines compared with single drug treatments, as indicated by flow cytometric and gene expression analysis.ResultsThe mRNA expression of Bax and P53 genes were significantly upregulated while Bcl-2, iNOS, and Cox-2 were significantly downregulated in all treatment groups compared with normal cells. The percentages of late apoptotic HepG2 and MCF-7 cells were higher in all treatment groups, particularly in the combination treatment group. Calculations for the combination index (CI) revealed a synergistic effect between both drugs for HepG2 cells (CI = 0.14) and MCF-7 cells (CI = 0.22).ConclusionOur data show that metformin, D-limonene, and their combinations exerted significant antitumor effects on the cancer cell lines by inducing apoptosis and modulating the expression of apoptotic genes.

Production of highly cytotoxic and low immunogenic L-asparaginase from Stenotrophomonas maltophilia EMCC2297

L-asparaginase is an important therapeutic enzyme that is frequently utilized in the chemotherapy regimens of adults as well as pediatric patients with acute lymphoblastic leukemia. However, a high rate of hypersensitivity with prolonged use has limited its utilization. Stenotrophomonas maltophilia (S. maltophilia) EMCC2297 isolate was reported as a novel and promising source for L- asparaginase. The present study aimed at the production, purification, and characterization of L- asparaginase from S. maltophilia EMCC2297 isolate. The microbial production of L-asparaginase by the test isolate could be increased by pre-exposure to chloramphenicol at 200 µg/ml concentration. S. maltophilia EMCC2297 L-asparaginase could be purified to homogeneity by ammonium sulphate precipitation and the purified form obtained by gel exclusion chromatography showed total activity of 96.4375 IU/ml and specific activity of 36.251 IU/mg protein. SDS-PAGE analysis revealed that the purified form of the enzyme is separated at an apparent molecular weight of 17 KDa. Michaelis-Menten constant analysis showed a Km value of 4.16 × 10− 2 M with L-asparagine as substrate and Vmax of 10.67 IU/ml. The antitumor activity of the purified enzyme was evaluated on different cell lines and revealed low IC50 of 2.2 IU/ml and 2.83 IU/ml for Hepatocellular cancer cell line (HepG-2), human leukemia cancer cell line (K-562), respectively whereas no cytotoxic effect could be detected on normal human lung fibroblast cells (MRC-5). However, mice treated with native L-asparaginase showed lower IgG titre compared to commercial L-asparaginase. This study highlights the promising characteristics of this enzyme making it a valuable candidate for further research and development to be an adduct in cancer chemotherapy.

Anticancer activity of 8-hydroxyquinoline-triphenylphosphine rhodium(III) complexes targeting mitophagy pathways

Metallodrugs exhibiting distinct mechanisms of action compared with cisplatin hold promise for overcoming cisplatin resistance and improving the efficacy of anticancer drugs. In this study, a new series of rhodium (Rh)(III) complexes containing tris(triphenylphosphine)rhodium(I) chloride [(TPP)3RhCl] (TPP = triphenylphosphine, TPP=O = triphenylphosphine oxide) and 8-hydroxyquinoline derivatives (H-XR1–H-XR4), namely [Rh(XR1)2(TPP)Cl]·(TPP=O) (Yulin Normal University-1a [YNU-1a]), [Rh(XR2)2(TPP)Cl] (YNU-1b), [Rh(XR3)2(TPP)Cl] (YNU-1c), and [Rh(XR4)2(TPP)Cl] (YNU-1d), was synthesized and characterized via X-ray diffraction, mass spectrometry and IR. The cytotoxicity of the compounds YNU-1a–YNU-1d in Hep-G2 and HCC1806 human cancer cell lines and normal HL-7702 cell line was evaluated. YNU-1c exhibited cytotoxicity and selectivity in HCC1806 cells (IC50 = 0.13 ± 0.06 μM, selectivity factor (SF) = 384.6). The compounds YNU-1b and YNU-1c, which were selected for mechanistic studies, induced the activation of apoptotic pathways and mitophagy. In addition, these compounds released cytochrome c, cleaved caspase-3/pro-caspase-3 and downregulated the levels of mitochondrial respiratory chain complexes I/IV (M1 and M4) and ATP. The compound YNU-1c, which was selected for in vivo experiments, exhibited tumor growth inhibition (58.9 %). Importantly, hematoxylin and eosin staining and TUNEL revealed that HCC1806 tumor tissues exhibited significant apoptotic characteristics. YNU-1a–YNU-1d compounds are promising drug candidates that can be used to overcome cisplatin resistance.

Cytotoxic potential and metabolomic profiling of alkaloid rich fraction of Tylophora indica leaves

Tylophora indica (Burm f.) Merrill, belong to family Asclepiadaceae, is considered to be a natural remedy with high medicinal benefits. The objective of this work is to assess the metabolomic profile of T. indica leaves enriched in alkaloids, as well as to evaluate the in vitro cytotoxicity of these leaves using the MTT assay on human breast MCF-7 and liver HepG2 cancer cell lines. Dried leaves of T. indica were extracted by sonication, using methanol containing 2 % (v/v) of acetic acid and obtained fraction was characterized by HPTLC and UPLC-MS. The UPLC-MS study yielded a preliminary identification of 32 metabolites, with tylophorine, tylophorine B, tylophorinine, and tylophorinidine being the predominant metabolites. The cytotoxicity of the extract of T. indica was evaluated on HepG2 and MCF-7 cell lines, yielding inhibitory concentration (IC50) values of 75.71 μg/mL and 69.60 μg/mL, respectively. Data suggested that the phytochemical screening clearly showed presence of numerous secondary metabolites with moderate cytotoxic efficacy. In conclusion, the future prospects of T. indica appear promising for the advancement of phytopharmaceutical-based anticancer medications, as well as for the design of contemporary pharmaceuticals in the field of cancer chemotherapy.

Cerric ammonium nitrate catalyzed eco-friendly green synthesis of chitosan Schiff base using PEG-400 as an anticancer agent against gastric cancer cells via inhibiting EGFR

The present study was conducted to scrutinize the pharmacological effect of oxazole-embedded Chitosan as an anticancer agent against gastric cancer cells. This compound was synthesized using the classical Schiff base reaction but utilizing the novel green chemical process where cerric ammonium nitrate (CAN) was used as a catalyst in the PEG-400 as solvent media. The target compound was obtained with an excellent yield at the catalyst loading of 5% CAN concentration in 15 min. The Kinase-Glo Plus luminescence kinase assay kit was used to determine the EGFR inhibitory activity of compound 1 where it showed potent activity with IC50 of 2.14 µM. Its effect was also determined on the cellular viability of the Human gastric cancer cell line (SGC7901), liver cancer cell line (HepG2), and lung cancer cell line (A549), where it exhibits potent activity against SGC7901. The compound further showed the concentration-dependent inhibitory effect on migration and invasion of SGC7901. In RT-qPCR analysis, the compound showed induction of apoptosis of SGC7901 cells possibly by restoring the expression of Bcl-2 and Bax near to normal, and inhibition of the mRNA expression of EGFR in a concentration-dependent manner. KEY WORDS: Schiff base, Chitosan, EGFR, mRNA, apoptosis, Bcl-2 Bull. Chem. Soc. Ethiop. 2024, 38(4), 1091-1101. DOI: https://dx.doi.org/10.4314/bcse.v38i4.22

Design and In Vitro Activity of Furcellaran/Chitosan Multilayer Microcapsules for the Delivery of Glutathione and Empty Model Multilayer Microcapsules Based on Polysaccharides.

In this study, multilayer microcapsules (two-layer and four-layer) based on furcellaran (FUR) and chitosan (CHIT) were produced, enclosing a tripeptide with an antioxidant effect-glutathione-in different concentrations. In addition, for the first time, an empty, four-layer microcapsule based on CHIT and FUR (ECAPS) was obtained, which can be used to contain sensitive, active substances of a hydrophobic nature. Layering was monitored using zeta potential, and the presence of the resulting capsules was confirmed by SEM imaging. In the current study, we also investigated whether the studied capsules had any effect on the Hep G2 cancer cell line. An attempt was also made to identify the possible molecular mechanism(s) by which the examined capsules suppressed the growth of Hep G2 cells. In this report, we demonstrate that the capsules suppressed the growth of cancer cells. This mechanism was linked to the modulation of the AKT/PI3K signaling pathway and the induction of the G2/M arrest cell cycle. Furthermore, the results indicate that the tested multilayer microcapsules induced cell death through an apoptotic pathway.

Production of kojic acid by Aspergillus flavus OL314748 using box-Behnken statistical design and its antibacterial and anticancer applications using molecular docking technique

Kojic acid is a wonderful fungal secondary metabolite that has several applications in the food, medical, and agriculture sectors. Many human diseases become resistant to normal antibiotics and normal treatments. We need to search for alternative treatment sources and understand their mode of action. Aspergillus flavus ASU45 (OL314748) was isolated from the caraway rhizosphere as a non-aflatoxin producer and identified genetically using 18S rRNA gene sequencing. After applying the Box-Behnken statistical design to maximize KA production, the production raised from 39.96 to 81.59 g/l utilizing (g/l) glucose 150, yeast extract 5, KH2PO4 1, MgSO4.7H2O 2, and medium pH 3 with a coefficient (R2) of 98.45%. Extracted KA was characterized using FTIR, XRD, and a scanning electron microscope. Crystalized KA was an effective antibacterial agent against six human pathogenic bacteria (Bacillus cereus, Staphylococcus aureus, Escherichia coli, Klebsiella pneumonia, Serratia marcescens, and Serratia plymuthica). KA achieves high inhibition activity against Bacillus cereus, K. pneumonia, and S. plymuthica at 100 μg/ml concentration by 2.75, 2.85, and 2.85 compared with chloramphenicol which gives inhibition zones 1, 1.1, and 1.6, respectively. Crystalized KA had anticancer activity versus three types of cancer cell lines (Mcf-7, HepG2, and Huh7) and demonstrated high cytotoxic capabilities on HepG-2 cells that propose strong antitumor potent of KA versus hepatocellular carcinoma. The antibacterial and anticancer modes of action were illustrated using the molecular docking technique. Crystalized kojic acid from a biological source represented a promising microbial metabolite that could be utilized as an alternative antibacterial and anticancer agent effectively.

Phosphine‐Catalyzed 1,6‐Addition and Tandem Addition/Self‐Aldol Condensation Reactions of Para‐Quinone Methides with Thiols

AbstractPhosphine‐catalyzed chemodivergent reactions of para‐quinone methides (p‐QMs) affording a wide variety of diarylmethyl thioether derivatives have been reported. In the transformation presented in this work, P(4‐FC6H4)3 catalyzed the direct 1,6‐addition of p‐QMs with thiols, whereas P(4‐MeC6H4)3 promoted the tandem addition/self‐aldol condensation reactions of p‐QMs with 1,4‐dithiane‐2,5‐diol. Moreover, some of the obtained products were screened against cancer cell lines HepG2, NB4, and K562, and one was found to inhibit the proliferation of all the tested cancer cell types.

New 1,3,4‒oxadiazole Quinazolines as Potential Anticancer Agents: Design, Synthesis, Biological Evaluation, and In silico Studies.

A novel series of 1,3,4‒oxadiazole connected to derivatives of quinazolinone (7a-e and 8a-f) was synthesized in the current investigation, and its anticancer and Topoisomerase‒ II inhibitory activity was evaluated. These findings inspired the design, synthesis, and biological analysis of these 1,3,4‒oxadiazole-quinazolinone analogues as antiproliferative Topo‒II inhibitors. The novel compound structures were determined using mass spectrometry and spectral methods (IR, NMR: 1H & 13C). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide colourimetric assay has been used to evaluate the anticancer efficacy of these drugs, and Autodock 4.2 provides a description of the docking results. For the more active members, additional biological tests, such as the Topo‒II inhibition experiment, were performed. These compounds' physicochemical and ADMET characteristics were examined in more detail. In the experiment for antiproliferative activity, compounds 7d, 7e, 8c, 8e, and 8f demonstrated encouraging cytotoxicity findings against HCT‒116 and HepG2 cancer cell lines, with IC50 values ranging from 3.85 to 19.43 μM. Compounds 7d, 7e, and 8e were the most potent inhibitors of Topo II with IC50 values of 15.18, 17.55, and 12.59 μM, respectively. Additionally, the docked compound 8c showed the strongest conventional hydrogen bonds among the residues Leu507(B), Asn508(B), Asn520(B), and Glu522(B) in the Human topoisomerase‒IIβ active site in the DNA complex (4G0U) when compared to the findings of docking experiments. New findings have discovered the fact that fused 1,3,4‒oxadiazole bearing quinazolinone contributed great significance in the field of medicinal chemistry due to their diverse biological properties. Finally, the in silico pharmacokinetic profile of all the synthesized derivatives was estimated using SwissADME, where some of the compounds followed Lipinski, Veber, Egan, and Muegge rules without deviation. The result of this activity advises that with a simple modification in structure, a potent anticancer agent can be generated with good efficacy.

Compounds from aerial parts of Isodon lophanthoides and their effects of cytotoxicity and LPS‐induced IL‐1β and IL‐10 production in RAW 264.7 macrophages

AbstractThe bioassay‐guided isolation of compounds from the aerial parts of Isodon lophanthoides (IL) resulted in the identification of five compounds (1–5). The chemical structures of 1–5 were determined through spectral analyses and compared to those identified in the literature to be 4‐hydroxybenzoic acid (1), protocatechuic acid (2), rosmarinic acid (3), coetsoidin B (4), and coetsoidin A (5). Compounds 1, 4, and 5 were found for the first time in the aerial parts of IL. Compounds 1 and 2 displayed potent cytotoxic activity against A549, MCF‐7, HepG2, and HL60 cancer cell lines, with IC50 values ranging from 13.93 to 18.69 µm and from 11.97 to 18.30 µm, respectively. Compounds 1‒5 significantly inhibited LPS‐induced IL‐1β production in RAW 264.7 macrophages compared to the LPS 5 ng/mL control group, resulting in IL‐1β concentrations ranging from 34.92 to 46.91 pg/mL. Additionally, compounds 1‒5 exhibited notable stimulation of IL‐10 production, with IL‐10 levels ranging from 358.77 to 478.23 pg/mL, compared to the LPS 5 ng/mL control group. These findings highlight the potential of compounds 1‒5 and the IL extracts for the cytotoxic effects on cancer cell lines and on LPS‐induced IL‐1β and IL‐10 production in RAW 264.7 macrophages.

Sucrose esters of aryldihydronaphthalene-type lignans, and antitumor activity of extracts of Moltkiopsis ciliata (Forssk.) aerial parts

One new compound (3f-[(7′R,8′R)-4,4′-dihydroxy-5-methoxy-2,7′-cycloligna-7-en-9-methoxycarbonyl, 9′-carbonyl-O-] -β- D-fructofuranosyl- (2→1)-α- D-glucopyranoside) (Moltkiopsin A) (2) was isolated and identified from the extract of aerial parts of the wild Egyptian plant Moltkiopsis ciliata (Frossk.), family Boraginaceae, for the first time, along with two aryldihydronaphthalene lignans 3f→9′:6f→9-[(7′R,8′R)-4,4′- dihydroxy-3,3′,5-trimethoxy-2,7′-cycloligna-7-en-9,9′-dicarbonyl]-6g-acetyl-α-D-gluco pyranosyl-(1→2) -β-D-fructofuranoside (Trigonotin A) (1) which was reported for the first time from this plant species and a known compound 3f→9′:6f→9-[(7′R,8′R)-4,4′- dihydroxy-3,3′,5-trimethoxy-2,7′-cycloligna-7-en-9,9′-dicarbonyl]-α-D-gluco pyranosyl - (1→2)- β-D- fructofuranoside (Trigonotin C) (3). These compounds were separated and purified using different chromatographic techniques and their structures were elucidated by extensive 1D (1H and 13C NMR), and 2D NMR (COSY, HSQC, and HMBC), besides ESI-MS spectral methods. Extracts were screened as antioxidant, antitumor and antibacterial. The different extracts showed moderate to strong antioxidant capacities in DPPH assays. Ethyl acetate, methylene chloride and crude methanol extracts exhibited the most significant free radicals scavenging activity when compared to the standard antioxidant vitamin C. Hexane and butanol fractions showed the highest cytotoxicity against the cancer cell lines HepG2 and MCF-7.

Synthesis, anticancer evaluation, molecular docking and ADME study of novel pyrido[4ʹ,3ʹ:3,4]pyrazolo[1,5-a]pyrimidines as potential tropomyosin receptor kinase A (TrKA) inhibitors

The starting compound 3-amino-1,7-dihydro-4H-pyrazolo[4,3-c]pyridine-4,6(5H)-dione (1) is reacted with each of diketone and β-ketoester, forming pyridopyrazolo[1,5-a]pyrimidines 4a,b and 14a,b, respectively. The compounds 4 and 14 reacted with each of aromatic aldehyde and arenediazonium salt to give the respective arylidenes and arylhydrazo derivatives, respectively. The structure of the new products was established using spectroscopic techniques. The cytotoxic activity of selected targets was tested in vitro against three cancer cell lines MCF7, HepG2 and HCT116. The data obtained from enzymatic assays of TrKA indicated that compounds 7b and 16c have the strongest inhibitory effects on TrKA with IC50 = 0.064 ± 0.0037 μg/ml and IC50 = 0.047 ± 0.0027 μg/ml, respectively, compared to the standard drug Larotrectinib with IC50 = 0.034 ± 0.0021 μg/ml for the HepG2 cancer cell line. In cell cycle analysis, compounds 7b, 15b, 16a and 16c caused the greatest arrest in cell cycle at the G2/M phase. In addition, compound 15b has a higher apoptosis-inducing effect (36.72%) than compounds 7b (34.70%), 16a (21.14) and 16c (26.54%). Compounds 7b, 16a and 16c were shown fit tightly into the active site of the TrKA kinase crystal structure (PDB: 5H3Q). Also, ADME study was performed on some selected potent anticancer compounds described in this study.

Anticancer potential of folic acid functionalized Ag-Zn bimetallic nanoparticles

In the current study, silver-zinc bimetallic nanoparticles (BNPs) have been synthesized using folic acid (FA) for investigating their potential against HepG-2 cancer cell lines. These FA-Ag/Zn BNPs were prepared and characterized using different techniques. UV/Vis analysis indicated absorbance peaks at 360 nm and 440 nm confirming the presence of BNPs. FTIR analyses confirmed the formation of FA-Ag/Zn BNPs and SEM images revealed a grain-like morphology which is uniformly distributed throughout with a particle size of 65.22 nm. The XRD diffractogram revealed crystal structure of the said BNP’s as face-centered cubic (FCC) having a crystallite size of 23.29 nm. Synthesized nanoparticles (FA-Ag/Zn BNPs) were then tested for their anticancer potential i.e. cellular mitochondrial activity was measured using MTT assay with varied concentration of the synthesized BNPs from 10 to 400 µg/mL. Maximum cytotoxicity (CTY) was recorded for 400 µg/mL of BNPs showing a significant cytotoxicity against HepG-2 cells as compared to the control. The current study may be considered as a significant in providing alternative route for chemotherapy. This route would be much safer, cost-effective and feasible due to the production of reactive oxygen species (ROS) which eventually result in death of cancerous cells.

New Tin (IV) and Organotin (IV) Complexes with a Hybrid Thiosemicarbazone/Hydrazone Ligand: Synthesis, Crystal Structure, and Antiproliferative Activity.

Nowadays, the search for new chemotherapeutic agents with low toxicity and high selectivity is a major concern. In this paper, we report the synthesis and characterization of a hybrid thiosemicarbazone/hydrazone ligand in its neutral form (L1H2) and as the chloride salt ([L1H3]Cl)-, three diorganotin (IV) complexes, and one complex with Sn (IV). The compounds have been fully characterized by IR, mass spectra, 1H, 13C, and 119Sn NMR, 119Sn CP/MAS NMR, and by single crystal X-ray diffraction. The organotin compounds have the empirical formula [SnR2L1] (R = Me, Bu, and Ph), but in the solid state, they are polymeric species with seven coordination number due to weak coordination of the pyridine nitrogen, whereas in solution, the polymeric structure is lost to afford hexacoordinate monomeric species. Reaction with SnI4 yields complex [Sn (L1)2]·EtOH, with the metal in a distorted dodecahedral arrangement. We have evaluated the antiproliferative activity of the two forms of the ligands and the four coordination compounds against MDA-MB-231, HeLa, PC3, and HepG2 cancer cell lines, and WI-38 normal cell line, and all the compounds present higher activity than cisplatin, used as the standard control. To investigate the mode of action, we have selected the most active complex, containing phenyl substituents, and used the triple negative breast cancer cell line MDA-MB-231. The results show that the complex induces apoptotic cell death promoted by generation of reactive oxygen species and by disruption of mitochondrial membrane potential.