Cancer Cell Line A549 Research Articles

Some 2-(4-bromophenoxymethyl)-6-iodo-3-substituted quinazolin-4(3H)ones: Synthesis, cytotoxic activity, EGFR inhibition and molecular docking

Different 6-iodo-2-(4-bromophenyoxymethyl)-3-substituted quinazolin-4-ones were prepared and tested for their cytotoxic activity against MCF-7 (breast), A-549 (lung) and HCT-116 (colon) cancer cell lines as well as normal fibroblasts WI-38. They revealed promising activity specially against A-549 and HCT 116 compared to Erlotinib. Compounds eliciting high cytotoxicity were further tested for their EGFR inhibitory activity and it was found that compounds 8, 9, 11a, b revealed superior activity than Gefitinib. Molecular docking of these compounds at the active site of EGFR confirmed the obtained activity as they showed binding interactions with the key amino acids as that of co-crystallized ligand. Therefore, these compounds can be considered as a promising core for anticancer agents with EGFR inhibitory activity.

Chemical composition, in vitro and in silico evaluation of essential oil from Eucalyptus tereticornis leaves for lung cancer

Chemical composition of the essential oil (EO) of Eucalyptus tereticornis leaves was studied by gas chromatography–mass spectrometry. Forty-five constituents were identified in the oil hydrodistilled from the sample collected from Ghudda Village, Bathinda (Pb), India of which eucalyptol (34.39%) and ledol (9.92%) were the major constituents. In vitro antioxidant and anticancer potential of EO was analysed by DPPH 2,2-diphenylpicrylhydrazyl (DPPH) and MTT assay. The percentage free radical scavenging activity was found to be 63.77%. The antiproliferative activity was analysed using MTT assay in adenocarcinomic human alveolar basal epithelial A549 cancer cell line and showed IC50 value of 47.14 µg/ml. In silico study of EO, constituents were performed using Maestro 12.9 against EGFR (PDB ID-2RGP). Five constituents from EO showed high dockscore as compared to standard Mobicertinib which indicated the effectiveness of oil constituents against lung cancer.

Design and prediction of novel pyrazole derivatives as potential anti-cancer compounds based on 2D-QSAR study against PC-3, B16F10, K562, MDA-MB-231, A2780, ACHN and NUGC cancer cell lines

Despite the decades of scientific studies for developing promising new therapies, cancer remains a major cause of illness and mortality, worldwide. Several cancer types are the major topic of research in drug discovery programs due to their global incidence cases and growing frequency. In the present study, using two different statistical approaches PCA (principal component analysis) and PLS (partial least squares), six 2D-QSAR (quantitative structure activity relationship) models have been developed for the set of compounds retrieved against seven cancer cell lines vizPC-3, B16F10, K562, MDA-MB-231, A2780, and ACHN. For the creation and validation of 2D-QSAR models, OECD (Organization for Economic Co-operation and Development) requirements have been strictly followed. All of the generated 2D-QSAR models produce a significant and high correlation coefficient value with several other statistical parameters. Moreover, developed 2D-QSAR models have been used for activity predictions of in-house synthesized 63 pyrazole derivatives compounds. Precisely, most statistically significant and accepted2D-QSAR model generated for each cancer cell line has been used to predict the pIC50 value (anti-cancer activity) of all 63 synthesized pyrazole derivatives. Furthermore, designing of novel pyrazole derivatives has been carried out by substituting the essential functional groups based on the best derived 2D-QSAR models for each cancer cell line, more precisely, based on the most significant molecular descriptors with enhanced anti-cancer activity. Finally, the prediction of the new designed molecules reveals higher pIC50 than the standard compounds.

MIL-100(Fe) Sub-Micrometric Capsules as a Dual Drug Delivery System.

Nanoparticles of metal–organic frameworks (MOF NPs) are crystalline hybrid micro- or mesoporous nanomaterials that show great promise in biomedicine due to their significant drug loading ability and controlled release. Herein, we develop porous capsules from aggregate of nanoparticles of the iron carboxylate MIL-100(Fe) through a low-temperature spray-drying route. This enables the concomitant one-pot encapsulation of high loading of an antitumor drug, methotrexate, within the pores of the MOF NPs, and the collagenase enzyme (COL), inside the inter-particular mesoporous cavities, upon the formation of the capsule, enhancing tumor treatment. This association provides better control of the release of the active moieties, MTX and collagenase, in simulated body fluid conditions in comparison with the bare MOF NPs. In addition, the loaded MIL-100 capsules present, against the A-375 cancer cell line, selective toxicity nine times higher than for the normal HaCaT cells, suggesting that MTX@COL@MIL-100 capsules may have potential application in the selective treatment of cancer cells. We highlight that an appropriate level of collagenase activity remained after encapsulation using the spray dryer equipment. Therefore, this work describes a novel application of MOF-based capsules as a dual drug delivery system for cancer treatment.

Low-density lipoprotein encapsulated thiosemicarbazone metal complexes is active targeting vehicle for breast, lung, and prostate cancers

Cancer is a leading cause of death worldwide and affects society in terms of the number of lives lost. Current cancer treatments are based on conventional chemotherapy which is nonspecific in targeting cancer. Therefore, intensive efforts are underway to better target cancer-specific cells while minimizing the side effects on healthy tissues by using LDL particles as active drug delivery vehicles. The goal is to encapsulate anticancer agents thiosemicarbazone metal-ligand complexes into LDL particles to increase the cytotoxic effect of the agent by internalization through LDL receptors into MCF7, A549, and C42 cancer cell lines as segregate models for biological evaluations targeting tubulin. Zeta potential data of LDL-particles encapsulated anticancer agents showed an acceptable diameter range between 66–91 nm and uniform particle morphology. The results showed cell proliferation reduction in all tested cell lines. The IC50 values of LDL encapsulated thiosemicarbazone metal-ligand complexes treated with MCF7, A549, and C42 ranged between 1.18–6.61 µM, 1.17–9.66 µM, and 1.01–6.62 µM, respectively. Western blot analysis showed a potent decrease in tubulin expression when the cell lines were treated with LDL particles encapsulated with thiosemicarbazone metal-ligand complexes as anticancer agents. In conclusion, the data provide strong evidence that LDL particles are used as an active drug delivery strategy for cancer therapy.

Cytotoxicity, Apoptosis, Migration Inhibition, and Autophagy-Induced by Crude Ricin from Ricinus communis Seeds in A549 Lung Cancer Cell Lines.

BackgroundRicin protein derived from Ricinus communis seeds is known to have a high toxicity to humans and animals. Several studies revealed that ricin, belonging to ribosome inactivating protein-I, has cytotoxic properties against various types of cancer cell lines.Material/MethodsCrude ricin (CR) from the seeds of R. communis was investigated for its cytotoxicity on the A549 cancer cell lines using the MTS assay, and the cell death mechanism was explored using flow cytometry and Western blot methods. The cell migration was measured using a scratch/wound-healing method and the autophagy activity was explored using Western blotting.ResultsCR showed cytotoxicity against A549 cancer cell lines, with an IC50 of 40.94 ppm. CR induced apoptosis and necrosis, but apoptosis occurred more frequently than necrosis. Apoptosis induced by CR was mediated by the activation of caspase-9 and caspase-3. CR inhibited cell migration in a concentration- and time-dependent manner, with the highest effect occurred at the concentration of 1.0 ppm. The autophagic experiment showed that CR inhibited autophagy in A549 lung cancer cells by decreasing Beclin-1 levels while increasing Atg5 levels in a concentration-dependent manner and CR decreased LC3-II level while increasing p62 level. Cisplatin treatment also inhibited autophagy as it exhibited the same effect on those autophagic proteins as CR.ConclusionsOur findings suggest that CR might be a potential candidate for anticancer drugs, but further study is needed to verify its anticancer properties.

Enzymatic Active Release of Violacein Present in Nanostructured Lipid Carrier by Lipase Encapsulated in 3D-Bioprinted Chitosan-Hydroxypropyl Methylcellulose Matrix With Anticancer Activity.

Violacein (Viol) is a bacterial purple water-insoluble pigment synthesized by Chromobacterium violaceum and other microorganisms that display many beneficial therapeutic properties including anticancer activity. Viol was produced, purified in our laboratory, and encapsulated in a nanostructured lipid carrier (NLC). The NLC is composed of the solid lipid myristyl myristate, an oily lipid mixture composed of capric and caprylic acids, and the surfactant poloxamer P188. Dormant lipase from Rhizomucor miehei was incorporated into the NLC-Viol to develop an active release system. The NLC particle size determined by dynamic light scattering brings around 150 nm particle size and ζ≈ −9.0 mV with or without lipase, but the incorporation of lipase increase the PdI from 0.241 to 0.319 (≈32%). For scaffold development, a 2.5 hydroxypropyl methylcellulose/chitosan ratio was obtained after optimization of a composite for extrusion in a 3D-bioprinter developed and constructed in our laboratory. Final Viol encapsulation efficiency in the printings was over 90%. Kinetic release of the biodye at pH = 7.4 from the mesh containing NLC-lipase showed roughly 20% Viol fast release than without the enzyme. However, both Viol kinetic releases displayed similar profiles at pH = 5.0, where the lipase is inactive. The kinetic release of Viol from the NLC-matrices was modeled and the best correlation was found with the Korsmeyer-Peppas model (R2 = 0.95) with n < 0.5 suggesting a Fickian release of Viol from the matrices. Scanning Electron Microscope (SEM) images of the NLC-meshes showed significant differences before and after Viol’s release. Also, the presence of lipase dramatically increased the gaps in the interchain mesh. XRD and Fourier Transform Infrared (FTIR) analyses of the NLC-meshes showed a decrease in the crystalline structure of the composites with the incorporation of the NLC, and the decrease of myristyl myristate in the mesh can be attributed to the lipase activity. TGA profiles of the NLC-meshes showed high thermal stability than the individual components. Cytotoxic studies in A549 and HCT-116 cancer cell lines revealed high anticancer activity of the matrix mediated by mucoadhesive chitosan, plus the biological synergistic activities of violacein and lipase.

Cytotoxic constituents from the leaves and stems of Panax quinquefolius

Four new isolates including one new butanediamide glycoside (1), one new flavonoid glycoside (2) and two new flavonone glycosides (3, 4) were identified from the leaves and stems of Panax quinquefolius, among which 1 possessed the firstly reported N,N'-(5-hydroxy-1,3-phenylene) butanediamide skeleton with an unique 6/9 ranged dual-ring structure. The structures were elucidated by the NMR data, ECD analysis and chemical acid hydrolysis. All the compounds (1-4) were tested for their cytotoxicity against two human cancer cell lines of HepG2, A549 and HCT116 by the MTT method. Outstandingly, compound 1 exhibited targeted inhibitory proliferation of HCT116 cell with IC50 value of 12.1 μM, whereas compounds 3 and 4 exhibited targeted inhibitory proliferation of HepG2 cell with IC50 values of 15.3 and 17.3 μM, as well as no obvious cytotoxicity of compounds 1-4 against A549.

Improvement of anticancer effect of berberine by salt formation modifications

BackgroundBerberine is a quaternary isoquinoline alkaloid that possesses a significant therapeutic effect on a variety of cancers. However, due to poor bioavailability, an increased dose is often required to achieve therapeutic goals. To improve the activities of natural berberine, most modifications were focused on the positive isoquinoline unit by grafting long aliphatic chains or heterocycles. However, the negative part is ignored. At this point, the strategy of salt formation modifications with short- and medium-chain fatty acids was proposed in this article. PurposeUsing salt modification to enhance the antitumor activity of berberine and explore the mechanism. MethodsFour short- and medium-chain fatty acid salts of berberine were prepared from berberine hydrochloride by salt formation modification with the sodium salt of butyric, caproic, octanoic, and decanoic acid, respectively. The cytotoxicity of four berberine salts on B16-F10, A549, HepG2, and U373 cancer cell lines was explored. Through cell localization, Mitochondrial membrane potential assay, and Western blotting analysis explored the mechanism of berberine salt-induced apoptosis. Its anticancer activity in vivo was demonstrated by the mouse xenograft model. ResultsThe four berberine fatty acid salts exhibited an enhanced inhibitory effect on B16-F10, A549, HepG2, and U373 cancer cell lines, particularly on B16-F10 cells. Meanwhile, the four berberine fatty acid salts can inhibit the migration of B16-F10 cells. The four berberine fatty acid salts induce cancer cell apoptosis through the mitochondrial pathway, which was confirmed by the mitochondrial colocalization, the decreased mitochondrial membrane potential as well as activation of caspase-3, cytochrome C (Cyt-C), and down-regulated expression of B-cell lymphoma 2 (Bcl-2). Most importantly, the four berberine fatty acid salts inhibited tumor growth in the in vivo B16-F10 melanoma model without generating side effects intraperitoneally. ConclusionsThis study revealed that salt formation modification may be an effective strategy to optimize the anticancer property of berberine hydrochloride and demonstrated the four berberine fatty acid salts induced apoptosis through the mitochondrial apoptotic pathway.

Quantification of biomarkers and evaluation of antioxidant, anti-inflammatory, and cytotoxicity properties of Dodonaea viscosa grown in Saudi Arabia using HPTLC technique

Abstract Dodonaea viscosa (Sapindaceae) was collected from Riyadh, Saudi Arabia. For the simultaneous measurement of quercetin and kaempferol, a validated high-performance thin-layer chromatography (HPTLC) approach was devised in D. viscosa leaf extract. The antioxidant activity was evaluated using diphenyl 1-picrylhydrazyl (DPPH) and 2,2′-azino-bis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. Moreover, the cytotoxic effect was tested against three cancer cell lines A549, HepG2, and MDA-MB-231. The potential anti-inflammatory properties of different fractions of D. viscosa were also evaluated using lipopolysaccharide (LPS)-induced THP-1 macrophages cells. The test samples include a crude extract of leaves and its solvent-soluble fractions of D. viscosa. The results showed that the crude extract and its fractions exhibited various significant biological activities, the fraction of chloroform demonstrated the highest free radical scavenging activity with IC50 values: 172.2 and 257.7 µg/mL for both DPPH and ABTS tests. Additionally, the chloroform fraction had the greatest cytotoxic activity against MDA-MB-231 (IC50 values: 24.6 ± 0.4 µg/mL). Moreover, the chloroform fraction exhibited the highest downregulation of the LPS-induced expression of TNF-α and IL-6. Quercetin and kaempferol were estimated concurrently in leaves crude extract using a validated technique on an HPTLC plate (10 cm2 × 10 cm2) with a combination of toluene–ethyl acetate–formic acid (5:4:0.2; v/v/v) as the mobile phase and a λ max of 254 nm. The amount of quercetin and kaempferol was found to be 31.8 and 15.01 mg/g of dried leaf extract, respectively. The presence of high levels of quercetin and kaempferol in D. viscosa leaves extract could explain its remarkable antioxidant, cytotoxic, and anti-inflammatory effects. The devolved HPTLC method can be used for routine analysis and standardization of D. viscosa crude plant material, extracts, and/or finished products using quercetin and kaempferol as appropriate markers.

A thioredoxin reductase 1 inhibitor pyrano [3,2-a] phenazine inhibits A549 cells proliferation and migration through the induction of reactive oxygen species production.

Thioredoxin reductase 1 (TrxR1) inhibitor, pyrano [3,2-a] phenazine, named CPUL-1, was synthesized with potential anticancer activity. The aim of the present work was to explore the potential anti-proliferative and anti-metastatic ability of CPUL-1 against A549 cancer cell lines in vitro. First, Cell Counting Kit-8 (CCK8) assay was used to assess cell proliferation. The A549 cell migration was evaluated by wound healing assay and transwell assay. Second, the epithelial-mesenchymal transition (EMT)-related proteins in A549 cells treated with CPUL-1 were analyzed by western blot methods. Then, TrxR1 enzyme activity assay and reactive oxygen species (ROS) assay were conducted to evaluate the effect of CPUL-1 on TrxR1 inhibition and ROS levels. Finally, western blotting was used to explore the mechanism of CPUL-1. The study results revealed that the ability of cell proliferation and migration was decreased under CPUL-1 treatment. CPUL-1 could distinctly restrain the migration and invasion of A549 cells through inhibiting EMT process. The results of TrxR1 enzyme activity assay, ROS assay and western blotting showed that CPUL-1 influenced EMT via inducing ROS-mediated ERK/JNK signaling by inhibiting TrxR1 enzyme activity. Together, proliferation suppression and anti-metastasis activity of CPUL-1 in A549 cells were demonstrated by all the evidence. Our findings highlight the great potential of phenazine compound CPUL-1 to suppress A549 cells proliferation and metastasis.

Discovery and evaluation of cytisine N-isoflavones as novel EGFR/HER2 dual inhibitors

Aberrant signaling of EGFR (ErbB) family members, in particular epidermal growth factor receptor (EGFR) and human epidermal growth factor 2 (HER2), is associated with the occurrence and development of many types of human malignancies (e.g., breast, lung, and gastric cancers), and dual targeting of EGFR/HER2 by small-molecular inhibitors has proven to be an effective therapeutic approach for treating these cancers. Herein we extracted and isolated from the medicinal plant Sophora alopecuroides L. a new natural product, dubbed Cytisine N-methylene-(4′,7-dihydroxy-3′-methoxy)-isoflavone (CNI1) that features a unique molecular framework. Our biochemical kinase assay suggested that one of its derivative CNI3 exhibited the best, micromolar (μM) inhibition activities against the EGFR (IC50 of 1.1 μM; Ki of 0.6 μM) and HER2 (IC50 of 3.5 μM; Ki of 1.8 μM) kinases. By contrast, another derivative CNI4 was most potent in inhibiting the EGFR-overexpressing A431 cancer cell line (IC50 of 45.5 μM) and the HER2-overexpressing BT-474 cancer cell line (IC50 of 32.9 μM), while the respective cellular activities of Lapatinib (a marketed drug) were 24.9 and 20.3 μM under the same assay condition. Moreover, both CNI3 and CNI4 showed desirable anti-metastatic efficacy in another two breast cancer models (viz., MDA-MB-231 and 4T1). In addition, we explored the inhibitory mechanisms of the CNIs against EGFR and HER2 by molecular dynamics simulation and revealed a novel mode of action that engages the cytisine and chromone moieties in CNIs. By combining structure- and ligand-based analysis, we further rationally engineered a new CNI compound that exhibits considerably improved cytotoxicity against both types of A431 and BT-474 cancer cells. Our study demonstrates the CNI compounds as a new class of EGFR/HER2 dual inhibitors and paves a way for their further development.

Design and Synthesis of Carbothioamide/Carboxamide-Based Pyrazoline Analogs as Potential Anticancer Agents: Apoptosis, Molecular Docking, ADME Assay, and DNA Binding Studies.

To discover anticancer drugs with novel structures and expand our research scope, pyrazoline derivatives (3a–3l) were designed and synthesized through cyclization of chalcones with thiosemicarbazide/semicarbazide in CH3COOH as a solvent. All newly synthesized pyrazoline derivatives were fully characterized using several spectroscopic experiments such as 1H, 13C NMR, FT-IR spectroscopy, and mass analysis. By HPLC, the purity of all analogs was found above 95% and both lead compounds (3a and 3h) were also validated by HRMS. Anticancer activity of synthesized pyrazoline derivatives (3a–3l) was investigated by the MTT assay against the human lung cancer cell (A549), human cervical cancer cell (HeLa), and human primary normal lung cells (HFL-1). Staurosporine (STS) was used as a standard drug. The anticancer results showed that two potent analogs 3a and 3h exhibit excellent activity against A549 (IC50 = 13.49 ± 0.17 and 22.54 ± 0.25 μM) and HeLa cells (IC50 = 17.52 ± 0.09 and 24.14 ± 0.86 μM) and low toxicity against the HFL-1 (IC50 = 114.50 ± 0.01 and 173.20 ± 10 μM). The flow cytometry was further used to confirm the anticancer activity of potent derivatives against the A549 cancer cell line. DNA binding interaction of anticancer agents 3a and 3h with Ct-DNA has been carried out by absorption, fluorescence, EtBr (dye displacement assay), circular dichroism, cyclic voltammetry and time-resolved fluorescence, which showed noncovalent binding mode of interaction. Anticancer activity of both lead compounds (3a and 3h) may be attributed to DNA binding. The evaluation of the antioxidant potential of pyrazoline analogs 3a and 3h by 2,2-diphenyl-1-picrylhydrazyl free radical showed promising antioxidant activity with IC50 values of 0.132 ± 0.012 and 0.215 ± 0.025 μg/mL, respectively. In silico molecular docking of pyrazoline derivatives was also performed using autodock vina software against the DNA hexamer with PDB ID: 1Z3F and ADMET properties to explore their best hits.

Screening of Rhamnus Purpurea (Edgew.) Leaves for Antimicrobial, Antioxidant, and Cytotoxic Potential.

Exploring new antimicrobial and cytotoxic drugs has been one of the most active areas of research. Rhamnus purpurea (Edgew.) buckthorn (Rhamnaceae) is a wild shrub traditionally used in Pakistan for the treatment of various ailments including cancer and infectious diseases. The aim of this study is to find novel antimicrobial and cytotoxic agents of plant origin. The crude methanol extract and full range of fractions of R. purpurea leaves were screened for the said activities using in vitro antimicrobial, antioxidant, and cytotoxic models following standard protocols. The antimicrobial activity was evaluated using the agar well diffusion method, while the antioxidant activity was assessed with 1,1-diphenyl-2-picryl hydrazyl (DPPH) and ferric reducing antioxidant power (FRAP) assays. The cytotoxic effect was investigated against the human cancer cell lines i.e. Caco-2 (gut), A549 (lung), HepG2 (liver), and MDA-MB-231 (breast) by MTS assay. In addition, toxicity studies were conducted on renal and alveolar primary epithelial cells (HRPTEpiC and HPAEpiC, respectively). Phytochemical investigation showed the presence of secondary metabolites such as alkaloids, saponins, tannins, glycosides, phenols, carbohydrates, proteins, and flavonoids. The n-hexane and chloroform fractions showed significant activity against Staphylococcus aureus (MIC 0.60 and 0.68 mg/mL, respectively), Salmonella typhi (MIC 0.48 and 0.45 mg/mL, respectively), and Bacillus subtilis (MIC 0.54 and 0.76 mg/mL, respectively). Among fungal strains, crude methanol and chloroform fractions exhibited significant activity against Fusarium solani (MIC 0.53 and 0.44 mg/mL, respectively) and Aspergillus niger (MIC 0.47 and 0.42 mg/mL, respectively). The crude methanol, n-hexane and chloroform fractions revealed the highest antioxidant activity at 1000 μg/mL, compared to that of ascorbic acid. The n-hexane fraction showed a significant cytotoxic effect against Caco-2, A549, and HepG2 cell lines with IC50 values of 5.65 ± 0.88, 5.50 ± 0.90, and 4.95 ± 1.0 μg/mL, respectively. Similarly, the chloroform fraction depicted significant activity against Caco-2, A549, and HepG2 cell lines with IC50 values of 4.55 ± 1.25, 4.65 ± 1.55, and 2.85 ± 0.98 μg/mL, respectively. The crude methanol extract and almost all fractions exhibited the highest selectivity index (>2.0) for Caco-2, A549, and HepG2 cancer cell lines, providing safety data for this study. The results showed that R. purpurea leaves have excellent antimicrobial, antioxidant, and cytotoxic potential and warrant further studies to search for novel compounds for the said activities.

Abstract 5480: Aristolochic acid as a scaffold for antitumor drug development

Abstract We have synthesized an analog of aristolochic acid (AA) with potent growth inhibitory activity in various human cancer cell lines and report here on mechanistic studies of this potential therapeutic. AA is a natural product and the main active principle of Aristolochia plants, a known source of antitumor agents. In 1964 due to nephrotoxicity, drug development efforts with AA were terminated following Phase I clinical trial in patients with terminal cancer of different origin. Structure activity studies of AA species allowed us to select a structural analog of AA (RJ-34) that lacks the determinants responsible for the renal toxicity and carcinogenicity of the parent compound. Building further on our experience with AA molecules, we developed a synthetic approach that affords efficient high-yield synthesis of RJ-34. Its structure and purity has been confirmed by high-performance liquid chromatography, liquid chromatography coupled with two-stage mass spectrometry and high resolution nucleic magnetic resonance. Sulforhodamine B assay revealed that RJ-34 has growth inhibitory activity in A549 and HCT-15 human cancer cell lines comparable to or stronger than that of paclitaxel or topotecan. At five nanomolar, RJ-34 inhibited DNA synthesis and cut the growth of A549 cells by 50%, leading to cell cycle arrest in G1/M and G2/S, with apparent apoptosis at concentrations greater than 200 nanomolar. Notably, protein synthesis in cultured cells, as evaluated by puromycin labelling, remained unaffected. RJ-34 was screened against the NCI-60 cell line panel - encompassing sixty human cancer cell lines from various tissues - providing clues to its mechanisms of action; namely, that RJ-34 acts through inhibition of DNA topoisomerases I and II and/or DNA intercalation. Follow-up studies using purified calf Topo I and human Topo II alpha and various plasmid substrates confirmed the role of RJ-34 as a DNA intercalator and human Topoisomerase II alpha poison. The pattern of activity of RJ-34 in the NCI-60 panel was distinct from that of AA and aristolactam - another related compound - suggesting that RJ-34 acts by mechanisms distinct from AA. In summary, RJ-34— a non-nephrotoxic analog of aristolochic acid— has a potent growth inhibitory activity in various human cancer cell lines with a mechanism of action different from the parent AA. Moving forward, pre-clinical pharmacokinetics, safety and efficacy studies are necessary to establish the potential of RJ-34 for development as an anticancer therapeutic. Citation Format: Keiji Hashimoto, Rajesh Chennamshetti, Radha Bonala, Francis Johnson, Arthur P. Grollman, Viktoriya S. Sidorenko. Aristolochic acid as a scaffold for antitumor drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5480.

RETRACTED ARTICLE: Biosynthesis of Zn-doped CuFe2O4 nanoparticles and their cytotoxic activity

Zn-doped CuFe2O4 nanoparticles (NPs) were eco-friendly synthesized using plant extract. These nanoparticles were characterized by X-ray diffraction, Fourier-transform infrared spectroscopy, scanning electron microscope (SEM), energy-dispersive X-ray spectroscopy and thermal gravimetric analysis (TGA). SEM image showed spherical NPs with size range less than 30 nm. In the EDS diagram, the elements of zinc, copper, iron, and oxygen are shown. The cytotoxicity and anticancer properties of Zn-doped CuFe2O4 NPs were evaluated on macrophage normal cells and A549 lung cancer cells. The cytotoxic effects of Zn-doped CuFe2O4 and CuFe2O4 NPs on A549 cancer cell lines were analyzed. The Zn-doped CuFe2O4 and CuFe2O4 NPs demonstrated IC50 values 95.8 and 278.4 µg/mL on A549 cancer cell, respectively. Additionally, Zn-doped CuFe2O4 and CuFe2O4 NPs had IC80 values of 8.31 and 16.1 µg/mL on A549 cancer cell, respectively. Notably, doping Zn on CuFe2O4 NPs displayed better cytotoxic effects on A549 cancer cells compared with the CuFe2O4 NPs alone. Also spinel nanocrystals of Zn-doped CuFe2O4 (~ 13 nm) had a minimum toxicity (CC50 = 136.6 µg/mL) on macrophages J774 Cell Line.

Antiproliferative and cytotoxic effects of bioactive compounds isolated from Onosma bourgaei.

Onosma species have been used commonly for traditional medicine for years due to their bioactive compounds content. Onosma bourgaei aerial part was extracted with hexane and methanol successively. The methanol extract was subjected to chromatographic techniques to isolate allantoin (1), 3,4-dihydroxybenzaldehyde (2), luteolin-7-O-glucoside (3), apigenin-7-O-β-glucoside (4), diosmetin-7-O-β-glucoside (5), rosmarinic acid (6), and globoidnan A (7). The structure of isolated compounds were identified by spectroscopic techniques such as 1D-NMR, 2D-NMR, FTIR, and LC-TOF/MS/MS. Antiproliferative activity of extract and natural compounds were carried out using HeLa (human epithelial cervix adenocarcinoma, ATCC® CCL-2™), HT29 (human colorectal adenocarcinoma, ATCC® HTB38™), MCF7 (human mammary gland adenocarcinoma, ATCC® HTB22™), and A549 (human lung carcinoma, ATCC® CCL185™) cancerous cells and normal cells, FL (human epithelial amnion cell, ATCC® CCL62™). Lactate dehydrogenase (LDH) was performed for cytotoxicity. The compounds, 4, 6, and 7 displayed the strong antiproliferative activity against corresponding cell lines. Apigenin-7-O-β-glucoside (4) revealed the excellent activity on HeLa, HT29, A549, and MCF6 cancer cell lines with the values of (IC50, µM) 167.3, 196.8 181.1, and 203.5, respectively, compared standard compound, cisplatin.

Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents.

Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [3H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos.

Anti-inflammatory and cytotoxic chemical constituents from the trunks of Berberis wallichiana

The chemical compositions and biological activities of the Berberis wallichiana trunk were evaluated for the first time. The alkaloid berberine was found as the main constituent of this plant. In the essential oil fraction, safrole was the most abundant component. The isolated 8-oxypalmatine compound exhibited cytotoxic effects on all three cancer cell lines A549 (human lung carcinoma), MDA-MB-231 (human breast carcinoma), and DU145 (human prostate carcinoma), while berberine was the most active to DU145 cells (IC50 of 4.99 μM). This alkaloid compound also potently inhibited the production of nitric oxide with IC50 at 0.017 μM. These findings suggested that the trunks of B. wallichiana might be a good source of bioactive compounds.

Cytotoxic cardiac glycosides from the root of Streblus asper

Bioassay-guided separation of the root of Streblus asper led to the identification of six undescribed cardiac glycosides, including a rare cardiac glycoside dimer, along with twelve previously reported analogues. Their structures were determined on the basis of analyses of spectroscopic methods (1D and 2D-NMR spectroscopy), high-resolution electrospray ionization mass spectrometry (HRESIMS), circular dichroism (CD), and comparison of their spectroscopic data with previously reported data. Regarding their cytotoxic activities, microculture tetrazolium assays showed that all isolated cardiac glycosides strongly inhibited MCC-803, T24, SKOV-3, HepG2, Wi-38, and A549 cancer cell lines, with IC50 values ranging from 0.075 μM to 0.752 μM. One cardiac glycoside, a rare cardiac glycoside dimer, exhibited the strongest activity against the six cancer cell lines, with IC50 values ranging from 0.075 μM to 0.214 μM. In addition, the structure-activity relationships (SARs) of cardiac glycosides were investigated. In summary, S. asper showed marked cytotoxicity to several cancer cell lines, which could be meaningful for discovering new anticancer agents.