NCI-H460 Lung Cancer Research Articles

Self-microemulsifying drug delivery system-based gastroretentive in situ raft of pazopanib with enhanced solubility and bioavailability.

Pazopanib hydrochloride (PZH) is a Biopharmaceutics Classification System class II drug that faces challenges at the formulation forefront including low aqueous solubility (0.043 mg/mL) and poor oral bioavailability (14-39%). The present investigation aimed to develop a self-microemulsifying drug delivery system (SMEDDS) of PZH using a blend of Capryol® 90, Labrasol®, and propylene glycol to improve its solubility. Furthermore, a sustained-release SMEDDS-based gastroretentive floating system was developed and optimized using the Central Composite Design approach of DoE. The optimized SMEDDS-based in situ gelling raft, R-SM-PZH, exhibited minimal floating lag time (3.09 ± 0.8 s), optimal viscosity (1229.4 ± 20.9 cP) and density (0.327 ± 0.15 g/mL) as compared to other formulations under study. Additionally, R-SM-PZH was evaluated for its in vitro dissolution in FaSSGF and FeSSGF, pharmacokinetic profile, and MTT assay (against NCI-H460 lung cancer cells) compared to pure PZH. A 12 h sustained release, three-fold augmentation in dissolution rate and bioavailability, and 15-fold enhancement in cytotoxicity were observed in comparison to pure PZH. Thus, the SMEDDS-based in situ gelling raft presents a promising approach to advancing the developability potential of PZH.

Suppression of Metastasis and Angiogenesis by Taxifolin Ruthenium-p-cymene Loaded PLGA Nanoparticles in Lung Carcinoma.

Flavonoid-based organometallic complexes were revealed to be novel bioactive compounds. The taxifolin ruthenium-p-cymene nanoparticle (TaxRu-NPs) was produced in this study, and the toxicological assessment was done prior to in vivo chemotherapeutic research. Furthermore, the in vitro chemotherapeutic investigation used the A549 and NCI-H460 lung cancer cell lines. The in vitro study found that TaxRu-NPs induced apoptosis in lung cancer cells and hindered their ability to form colonies and migrate. The in vivo study showed that treatment with TaxRu-NPs restored the histological structure of a normal lung with less hyperplasia and lymphocytic infiltration. Furthermore, the treatment downregulated the angiogenic marker VEGF and the cell survival protein β-catenin and upregulated apoptotic markers like p53 and caspase-3. TaxRu-NPs treatment additionally raised the apoptotic index and decreased cancer cell growth. Finally, TaxRu-NPs effectively alleviate lung cancer by activating p53-mediated apoptosis and preventing angiogenesis and metastasis by decreasing the VEGF/β-catenin pathway.

The up-regulation of PD-L1 during boningmycin-induced senescence in human cancer cells depends on the activation of the JAK/STAT signaling pathway mediated by SASP.

Therapy-induced senescence can regulate both the innate and adaptive immune systems, thereby affecting therapeutic efficacy. Bleomycin is a major component of combined chemotherapy regimens, utilized for the treatment of multiple tumors, whereas pulmonary toxicity severely restricts its clinical benefits. As a member of the bleomycin family, boningmycin (BON) exhibits potent anticancer activity with minimal pulmonary toxicity, making it a potential alternative to bleomycin. Low concentrations of BON can induce senescence, but the impact of BON-induced senescence on anticancer immunity remains unclear. This study investigates the effects of BON-induced senescence on PD-L1 expression and the underlying mechanisms in human cancer cells. Firstly, the elevation of PD-L1 protein during BON-induced senescence was confirmed by a senescence β-galactosidase staining assay, detection of the senescence-associated secretory phenotype (SASP), western blot and flow cytometry in human lung cancer NCI-H460 cells and breast cancer MDA-MB-231 cells. Subsequently, it was shown that the increase in PD-L1 protein is mediated by SASP, as evidenced by the use of conditional media, knockdown of cyclic GMP-AMP synthase and inhibition of stimulator of interferon genes. Ultimately, it was demonstrated that SASP-mediated PD-L1 up-regulation is dependent on the activation of the JAK/STAT pathway through the use of specific inhibitors and siRNAs. These findings clarify the impact of BON-induced senescence on PD-L1 expression and may contribute to the optimization of the therapeutic efficacy of bleomycin-related compounds and the clinical transformation of BON.

Ginsenoside Rb1 Inhibits the Proliferation of Lung Cancer Cells by Inducing the Mitochondrial-mediated Apoptosis Pathway.

Lung cancer is one of the more common malignant tumors posing a great threat to human life, and it is very urgent to find safe and effective therapeutic drugs. The antitumor effect of ginsenosides has been reported to be a treatment with a strong effect and a high safety profile. This paper aimed to investigate the inhibitory effect of ginsenoside Rb1 on 95D and NCI-H460 lung cancer cells and its pathway to promote apoptosis. We performed the CCK-8 assay, fluorescence staining assay, flow cytometry, scratch healing assay, and Transwell assay to detect the effects of different concentrations of ginsenoside Rb1 on the antitumor activity of 95D and NCI-H460 cells and Western Blot detected the mechanism of antitumor effect. Ginsenoside Rb1 treatment significantly increased the inhibition and apoptosis rates of 95D and NCIH460 cells and inhibited the cell cycle transition from S phase to G2/M. Rb1 induces apoptosis by altering the levels of P53, Bax, Cyto-c, Caspase-8, Caspase-3, Cleaved Caspase-3, Bcl-2, MMP-2, and MMP-9 proteins and activating the external apoptotic pathway. Ginsenoside Rb1 inhibits proliferation and migration and induces apoptosis of 95D and NCI-H460 lung cancer cells by regulating the mitochondrial apoptotic pathway to achieve antitumor activity.

Evaluation of Anti-Cancer Potential of Homeopathic Medicines by In-Vitro Study on Human Breast, Lung and Colorectal Cancer Cells

The purpose of this study is to assess the cytotoxic effects of homoeopathic drugs on cancer cell lines by In-vitro experiment. Background: Homoeopathy is a renowned therapeutic approach in many nations across the world. However, the approach has sparked much scientific discussion concerning its efficacy and methods of action. This is particularly true when it comes to the application of homeopathy in cancer treatment. Objective: The purpose of this study was to evaluate the cytotoxic effect of homoeopathic remedies on cancer cells and to emphasise the therapeutic effects of 50 Millesimal potencies. Materials & Methods: Carcinosinum, Conium maculatum, and Asterias rubens were the drugs used in 0/1 potency against the MCF 7 breast cancer cell line. Carcinosinum, Nitric acid, and Ruta were the drugs in 0/1 potency used against the HCT 116 colorectal cancer cell line and the NCI-H460 lung cancer cell line. 90% alcohol medicated on poppy-sized globules, dried fully and used as a control for all cell lines. The cytotoxicity has been assessed using the standard MTT test. Results: The LC50 values of the medicines tested on breast and lung cancer cells were not obtained up to 40000 ppm concentrations, as a result, cytotoxicity evaluation was not possible. The LC50 values of the medicines tested on Colo-rectal cancer cells were obtained around 20,000 ppm concentration and showed a gradual increase in Cell Death with increasing Concentration of exposure of the drugs. As a result, these drugs revealed cytotoxic qualities as well as anti-cancer actions. Conclusion: Despite the objective facts, we cannot reach a definite conclusion about the anti-cancer effectiveness of these drugs in vitro because several aspects of homeopathy's action are unlikely to be replicated in In-vitro study. Determination of reasons for the same or understanding the molecular mechanism of resistance of the cell lines to the cytotoxic effects of the drugs were not within the purview of the study and these can be addressed in future studies. Keywords: Homeopathy, Cancer, MCF-7, HCT 116, NCI-H 460, In-Vitro, Carcinosinum, Conium maculatum, Asteria rubens, Ruta graveolens, Nitric acid, 50 Millesimal Potency, MTT Assay.

Cytotoxic constituents from the fruit of Solanum aculeastrum

A new triterpene, aculeastrumone A (1), a new triterpene saponin aculeastrumoside A (2), and eleven known compounds (3–13) were isolated from MeOH/Water (80/20) extract of the fruits of Solanum aculeastrum (Solanaceae). Their structures were established by detailed 1D and 2D NMR spectroscopic studies and mass spectrometry. The isolated compounds were evaluated against three human cancer cells ((MCF-7 (breast cancer), NCI-H460 (lung cancer), and Hela (cervical cancer)) and normal human fibroblast (BJ) cell lines. Among them, saponins 2–5, 7–8, and Carpesterol 10 possess significant cytotoxic activity with IC50 ≤ 10 µM against the three cancer cell lines.

Anti-cancer activity and mechanism of flurbiprofen organoselenium compound RY-1-92 in non-small cell lung cancer.

Lung cancer is one of the malignancies with the highest incidence and mortality rates worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancer types. In this study, the anti-cancer activities of a novel flurbiprofen organic selenium compound, RY-1-92, on NSCLC cells and a mouse model and the underlying molecular mechanisms were explored. We found that compound RY-1-92 can significantly inhibit the viability, colony formation and migration of A549, NCI-H460 lung cancer cells. Flow cytometry analysis showed that RY-1-92 also can lead to G2/M cell cycle arrest and apoptosis induced in lung cancer cells. Further, RY-1-92 can decrease the tumor size in the Lewis lung cancer tumor-bearing mouse model. The protein levels of cell cycle-related proteins CDK1/cyclinB1 were decreased, while the apoptosis-related protein BAX was increased dramatically after RY-1-92 treatment in vitro and in vivo. Impressively, it was found that TRPV1 might act as a potential molecular target of RY-1-92 using the SEA search server. Furthermore, down-regulation on TRPV1 and its downstream associated factors including p-AKT protein and MAPK signaling pathway-related proteins after RY-1-92 treatment was observed in A549, NCI-H460 lung cancer cells. Taken together, our findings shed light on the potential of RY-1-92 as a novel small molecular drug for NSCLC, and it is of great significance for its further in-depth research and development.

Proteomic analysis reveals the molecular mechanism of Astragaloside in the treatment of non-small cell lung cancer by inducing apoptosis

BackgroundAstragaloside III (AS III), a saponin-like metabolite derived from the traditional Chinese medicine Astragali Radix, has been shown to be effective in the treatment of cancer and heart failure, and a variety of digestive disorders. However, its molecular mechanism in the treatment of non-small cell lung cancer (NSCLC) is unknown.MethodsHuman lung cancer A549 cells and NCI-H460 cells and a normal human lung epithelial cell BEAS-2B were treated with different concentrations of AS III. CCK-8 and EdU staining were used to determine the anti-proliferative effects of AS III in vitro. Quantitative proteomic analysis was performed on A549 cells treated with the indicated concentrations of AS III, and the expression levels of apoptosis-related proteins were examined by Western blotting.ResultsAS III treatment significantly inhibited proliferation and increased apoptosis in A549 and H460 cells and modulated functional signaling pathways associated with apoptosis and metabolism. At the molecular level, AS III promoted a reduction in the expression of ANXA1 (p < 0.01), with increased levels of cleaved Caspase 3 and PARP 1. In addition, AS III treatment significantly decreased the LC3-I/LC3-II ratio. The results of experiment in vitro showed that AS III promoted NSCLC apoptosis by down-regulating the phosphorylation levels of P38, JNK, and AKT (p < 0.01), inhibiting the expression of Bcl-2 (p < 0.01), and up-regulating the expression of Bax (p < 0.01).ConclusionThese findings provide a mechanism whereby AS III treatment induces apoptosis in NSCLC cells, which may be achieved in part via modulation of the P38, ERK and mTOR signaling pathways.

3,3',5,5'-Tetramethoxybiphenyl-4,4'diol triggers oxidative stress, metabolic changes, and apoptosis-like process by reducing the PI3K/AKT/NF-κB pathway in the NCI-H460 lung cancer cell line

Lung cancer is one of the leading causes of cancer-related deaths in men and women worldwide. Current treatments have limited efficacy, cause significant side effects, and cells can develop drug resistance. New therapeutic strategies are needed to discover alternative anticancer agents with high efficacy and low-toxicity. TMBP, a biphenyl obtained by laccase-biotransformation of 2,6-dimethoxyphenol, possesses antitumor activity against A549 adenocarcinoma cells. Without causing damage to sheep erythrocytes and mouse peritoneal macrophages of BALB/c mice. In addition to being classified as a good oral drug according to in-silico studies. This study evaluated the in-vitro cytotoxic effect of TMBP on lung-cancer cell-line NCI-H460 and reports mechanisms on immunomodulation and cell death. TMBP treatment (12.5–200 μM) inhibited cell proliferation at 24, 48, and 72 h. After 24-h treatment, TMBP at IC50 (154 μM) induced various morphological and ultrastructural changes in NCI-H460, reduced migration and immunofluorescence staining of N-cadherin and β-catenin, induced increased reactive oxygen species and nitric oxide with reduced superoxide radical-anion, increased superoxide dismutase activity and reduced glutathione reductase. Treatment also caused metabolic stress, reduced glucose-uptake, intracellular lactate dehydrogenase and lactate levels, mitochondrial depolarization, increased lipid droplets, and autophagic vacuoles. TMBP induced cell-cycle arrest in the G2/M phase, death by apoptosis, increased caspase-3/7, and reduced STAT-3 immunofluorescence staining. The anticancer effect was accompanied by decreasing PI3K, AKT, ARG-1, and NF-κB levels, and increasing iNOS. These results suggest its potential as a candidate for use in future lung anticancer drug design studies.

Schweinfurthiamide, a new alkaloid isolated from the tuber roots of Asparagus flagellaris Baker (Liliaceae)

The phytochemical investigations of the tuber roots of Asparagus flagellaris led to the isolation of a new alkaloid, schweinfurthiamide (1) and eight known compounds. The structures of the isolated compounds were elucidated using spectroscopic techniques 1D and 2D NMR (1H, 13C, COSY, HMBC, HMQC, HSQC-TOCSY). The absolute configuration of 1 was unambiguously determined using DP4+ calculations. Compound 1 showed significant cytotoxicity against MCF-7 (breast cancer), NCI-H460 (lung cancer), and Hela (cervical cancer) cancer cell lines with IC50 values of 1.18 ± 0.02 µM, 2.25 ± 0.19 µM, and 4.23 ± 0.26 µM, respectively and no toxicity against normal human fibroblast (BJ).

Regulation of cytokinesis and necroptosis pathways by diosgenin inhibits the proliferation of NCI-H460 lung cancer cells

AimOvercoming resistance to apoptosis and antimitotic chemotherapy is crucial for effective treatment of lung cancer. Diosgenin (DG), a promising phytochemical, can regulate various molecular pathways implicated in tumor formation and progression. However, the precise biological activity of DG in lung cancer remains unclear. This study aimed to investigate the antiproliferative activity of DG in NCI-H460 lung carcinoma cells to explore the underlying antimitotic mechanisms and alternative cell death pathways. Materials and methodsIn a 2D culture system, we analyzed cell viability, multinucleated cell frequency, cell concentration, cell cycle changes, cell death induction, intracellular reactive oxygen species (ROS) production, and nuclear DNA damage, particularly in relation to target gene expression. We also evaluated the antiproliferative activity of DG in a 3D culture system of spheroids, assessing volume changes, cell death induction, and inhibition of proliferation recovery and clonogenic growth. Key findingsDG reduced cell viability and concentration while increasing the frequency of cells with multiple nuclei, particularly binucleated cells resulting from daughter cell fusion. This effect was associated with genes involved in cytokinesis regulation (RAB35, OCRL, BIRC5, and AURKB). Additionally, DG-induced cell death was linked to necroptosis, as evidenced by increased intracellular ROS production and RIPK3, MLKL, TRAF2, and HSPA5 gene expression. In tumor spheroids, DG increased spheroid volume, induced cell death, and inhibited proliferation recovery and clonogenic growth. SignificanceOur study provides new insights into the biological activities of DG in lung cancer cells, contributing to the development of novel oncological therapies.

How do prolonged anchorage-free lifetimes strengthen non-small-cell lung cancer cells to evade anoikis? – A link with altered cellular metabolomics

BackgroundMalignant cells adopt anoikis resistance to survive anchorage-free stresses and initiate cancer metastasis. It is still unknown how varying periods of anchorage loss contribute to anoikis resistance, cell migration, and metabolic reprogramming of cancerous cells.ResultsOur study demonstrated that prolonging the anchorage-free lifetime of non-small-cell lung cancer NCI-H460 cells for 7 days strengthened anoikis resistance, as shown by higher half-life and capability to survive and grow without anchorage, compared to wild-type cells or those losing anchorage for 3 days. While the prolonged anchorage-free lifetime was responsible for the increased aggressive feature of survival cells to perform rapid 3-dimensional migration during the first 3 h of a transwell assay, no significant influence was observed with 2-dimensional surface migration detected at 12 and 24 h by a wound-healing method. Metabolomics analysis revealed significant alteration in the intracellular levels of six (oxalic acid, cholesterol, 1-ethylpyrrolidine, 1-(3-methylbutyl)-2,3,4,6-tetramethylbenzene, β-alanine, and putrescine) among all 37 identified metabolites during 7 days without anchorage. Based on significance values, enrichment ratios, and impact scores of all metabolites and their associated pathways, three principal metabolic activities (non-standard amino acid metabolism, cell membrane biosynthesis, and oxidative stress response) offered potential links with anoikis resistance.ConclusionsThese findings further our insights into the evolution of anoikis resistance in lung cancer cells and identify promising biomarkers for early lung cancer diagnosis.

Cytotoxic Activity of Vitex leucoxylon Aqueous Leaf Extract Against A549 and NCIH-460 Lung Cancer Cell Lines

The primary goal of this research was to determine the cytotoxic potential of an aqueous extract of Vitex leucoxylon aerial parts on the lung cancer A549 and non-small cell lung cancer NCIH-460 cell lines. The Soxhlet apparatus and distilled water were used for the extraction of the medicinal plant. The MTT in vitro assay was used to test the compounds for anticancer activity against two different lines of lung cancer. The cytotoxic activity of V. leucoxylon in the present study was very substantial as measured by its ability to suppress the growth of both cell lines. The IC50 values for A549 and NCI-H460 were determined to be 315.57 and 560.48 μg/mL, respectively. The current research confirmed that V. leucoxylon’s aqueous leaf extract possessed potent anticancer properties. Both the cancer cell lines were significantly inhibited in their ability to differentiate when subjected to the MTT assay. In future, flavonoid compounds in the aqueous extract need to be purified, characterized, and structurally elucidated for in-vivo studies, which could lead to the creation of new drug candidates.

Abstract 3091: Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068

Abstract WEE1 is activated upon DNA damage and regulates the G2/M cell cycle checkpoints. Inhibition of WEE1, in conjunction with genetic alterations and/or a DNA damaging agent, could result in mitotic catastrophe and apoptosis of cancer cells, offering an attractive approach to treat cancer. Small molecule WEE1 inhibitors, such as AZD1775, showed good clinical POC (proof of concept) data in several tumors including ovarian, colon, and uterine carcinoma. We have identified a novel, potent, and highly selective WEE1 inhibitor IMP7068. Herein we will present its discovery and IND enabling in vitro and in vivo studies. IMP7068 exhibits superior WEE1/PLK1 selectivity (&amp;gt;435 fold) compared to AZD1775. IMP7068 also shows potent cytotoxicity against a wide range of cancer cell lines. In addition, IMP7068 has desirable PK profiles with long half-life and high exposure in preclinical species. Anti-tumor efficacy of IMP7068 has been demonstrated in mice CDX models of colorectal LoVo, non-small cell lung cancer NCI-H1299 and a PDX model of uterine UT5318 with good dose-response tumor inhibition and tolerability. IMP7068 is currently in a phase I study to evaluate its safety, tolerability, pharmacokinetics, and anti-tumor activity in patients with advanced solid tumors (ClinicalTrials.gov Identifier: NCT04768868). Citation Format: Sui Xiong Cai, Ning Ma, Xiaozhu Wang, Yangzhen Jiang, Hongxia Zhang, Mingchuan Guo, Ruiyu Zhou, Ye Edward Tian. Discovery and development of a potent and highly selective WEE1 inhibitor IMP7068 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3091.

Development of certain aminoquinazoline scaffolds as potential multitarget anticancer agents with apoptotic and anti-proliferative effects: Design, synthesis and biological evaluation

Newly designed 4 - aminoquinazoline derivatives (5a-f, 6a, b, 7, 8, 9, 10a-c, 11a, b, 12a, b and 13a, b) have been synthesized and evaluated for their potential multitarget anticancer activities, apoptotic and anti-proliferative effects. Thereupon, in vitro cytotoxic activities of all the synthesized compounds were screened against NCI 60 human cancer cell lines (nine subpanels) at NCI, USA. Successfully, 2-morpholino-N-(quinazolin-4-yl) acetohydrazide 5e was granted an NSC code, owing to its significant potency and broad spectrum of activity against various cancer cell lines; leukemia K-562, non-small cell lung cancer NCI-H522 cells, colon cancer SW-620, melanoma LOX IMVI, MALME-3M, renal cancer RXF 393, ACHN and breast cancer MDA-MB231/ATCC (GI% = 99.6, 161, 126.03, 90.22, 174.47, 139.7, 191 and 97, respectively). Compound 5e showed the best inhibitory activity (GI50 = 1.3 µM) against melanoma LOX IMVI, when tested at five doses against NCI 60 cell lines. Furthermore, compound 5e showed comparable EGFR and CDK2 inhibitory activity results (IC50 = 0.093 ± 0.006 μM and 0.143 ± 0.008 μM, respectively) to those of lapatinib and ribociclib (IC50 = 0.03 ± 0.002 μM and 0.067 ± 0.004 μM, respectively). Western blotting analysis of compound 5e against melanoma LOX IMVI marked out significant reduced EGFR and CDK2 protein expression percentages, up to 32.97% and 34.09%, respectively, if compared to lapatinib (31.18%) and ribociclib (29.66%). Moreover, compound 5e caused clear cell cycle arrests at S phase of renal UO-31 cells and at G1 phase of both breast cancer MCF7 and ovarian cancer IGROV1, associated with remarkable increase of DNA content of the controls. In accordance, it demonstrated promising anti- proliferative and apoptotic activities, showing a significant increase in total apoptotic percentages of renal cancer UO-31, breast cancer MCF7 and ovarian IGROV1 cancer cell lines, if compared to the control untreated cells (from 1.79% to 46.72%, 2.19% to 39.02% and 1.66 to 42.51%, respectively). Molecular modelling and dynamic simulation study results supported the main objectives of the present work.

Screening of Anti-cancer Activity of rGO–Bi2O3 Nanocomposite on Apoptosis in A549 and NCI-H460 Lung Cancer Cell Lines

Screening of Anti-cancer Activity of rGO–Bi2O3 Nanocomposite on Apoptosis in A549 and NCI-H460 Lung Cancer Cell Lines

In vitro antioxidant, anti-inflammatory, and anticancer activities of mixture Thai medicinal plants

BackgroundThe phytochemical study of medicinal plants is rapidly gaining popularity with many pharmacologic effects. This study aims to determine the antioxidant capacity as well as anticancer and antimigration activities of Clear belongs Plus extract (CBL-P) which consisted of five medicinal plants namely, Alpinia galanga, Piper nigrum, Citrus aurantifolia, Tiliacora triandra, and Cannabis sativa on human colon cancer cells SW620 and HCT116 cell lines, and human non-small cell lung cancer cells A549 and NCI-H460 cell lines.MethodsIn this study the dried-plant powder was extracted using 90% ethanol. Additionally, CBL-P was studied antioxidative activity via DPPH and ABTS assays and anti-inflammatory activities using nitric oxide assay using Griess reaction. Antiproliferation and antimigration of CBL-P were investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) and scratch assay.ResultsThe results showed that CBL-P had potent antiproliferative activity with IC50 values in a concentration- and time-dependent manners for all four cell lines. CBL-P also possessed potent antimigration activity against all studied cancer cells. CBL-P demonstrated antimigration activity on four different types of cancer cells (A549, NCI-H460, HCT116, and SW620) after 48 h of incubation, with the greatest effect seen at the highest concentration tested (15 μg/mL) in A549 cells (10.23% of wound closure) and NCI-H460 cells (9.16% of wound closure). CBL-P was also effective in reducing migration in HCT116 and SW620 cells, with a range of closure area from 10—50%. In addition, CBL-P had antioxidant activity with IC50 values of 8.549 ± 0.241 mg/mL and 2.673 ± 0.437 mg/mL for DPPH and ABTS assays, respectively. CBL-P also showed anti-inflammatory activity with the best inhibitory activity on NO production at a concentration of 40 μg/mL.ConclusionIn conclusion, the mixture extract possessed antioxidant and anti-inflammatory activity. Furthermore, the mixture plant extract significantly exhibited antiproliferative and antimigration activities on SW620, HCT116, A549, and NCI-H460 cells (P ≤ 0.05). Taken together, our results suggest that medicinal plants may have synergistic effects that could potentially enhance the effectiveness of cancer treatment when used as adjuvants. These findings provide a solid scientific foundation for future efforts to explore the mechanism of action.

Tumor killing by a dietary curcumin mono-carbonyl analog that works as a selective ROS generator via TrxR inhibition

In comparison with normal cells, cancer cells feature intrinsic oxidative stress, thereby being more vulnerable to further production of reactive oxygen species (ROS) by pro-oxidative anticancer agents (PAAs). However, PAAs also inevitably generate ROS in normal cells, resulting in their narrow therapeutic window and toxic side effects that greatly limit their clinical application. To develop PAAs that generate ROS selectively in cancer cells over in normal cells, we rationally designed three series of 21 dietary curcumin 5-carbon mono-carbonyl analogs differentiated by either placement of the cyclohexanone, piperidone, and methylpiperidone linkers, or introduction of electron-withdrawing trifluoromethyl and electron-donating methoxyl groups on its two aromatic rings in the ortho, meta, or para position to the linkers. From the designed molecules, 2c, characterized of the presence of the meta-CF3-substituted mode and the piperidone linker, was identified as a potent selective ROS-generating agent, allowing its ability to kill selectively human non-small cell lung cancer NCI–H460 (IC50 = 0.44 μM) over human normal lung MRC-5 cells with a selectivity index of 32.0. Additionally, it was more potent and selective than the conventional chemotherapeutic agents (5-fluorouracil and camptothecin) did. Mechanistical investigation reveals that by means of its Michael acceptor unit and structure characteristics as described above, 2c could covalently modify the Sec-498 residue of intracellular thioredoxin reductase (TrxR) to generate ROS selectively, resulting in ROS-dependent apoptosis and ferroptosis of NCI–H460 cells. Noticeably, 2c inhibited significantly the growth of NCI–H460 cell xenograft tumor in nude mice without obvious toxicity to liver and kidney. Together, this work highlights a practical strategy of targeting TrxR overexpressed in cancer cells to develop PAAs capable of generating ROS selectively, as evidenced by the example of 2c.

Construction and validation of a novel tumor necrosis factor-related apoptosis-inducing ligand mutant MuR5S4-TR.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill tumor cells but has no significant effect on normal cells. However, the use of TRAIL is limited for resistance by more than 50% of the tumor cell lines. It's very important to develop a more efficient form of TRAIL for cancer treatment. The N-terminal in soluble fragments (114-281aa) of TRAIL was redesigned to construct a novel TRAIL mutant-MuR5S4-TR. The Cell Counting Kit-8 method to explore the antitumor effects. The potential mechanisms were also explored. Novel TRAIL mutant with cell-penetrating peptides (CPP) like and Second mitochondria-derived activator of caspases (Smac) like structure-MuR5S4-TR was successfully constructed. The prokaryotic expression system was successfully built, and the MuR5S4-TR was purified and reconfirmed by western blot. MuR5S4-TR could enhance the antitumor effects of TRAIL in most of the cancer cell lines significantly, NCI-H460 lung cancer cell line, for instance. After MuR5S4-TR treatment, the expressions of death receptor 4 (DR4), DR5, Caspase-8, and cleaved Caspase-3 were remarkably increased, however, there was no significant difference in X-linked inhibitor of apoptosis expression. We constructed a novel TRAIL mutant with CPP-like and Smac-like structure-MuR5S4-TR. The MuR5S4-TR showed significantly stronger antitumor effects than TRAIL in many tumor cell lines. The MuR5S4-TR showed strong antitumor effects both in vitro and in vivo. This preliminary study implies that MuR5S4-TR may be a more efficient form of TRAIL for cancer therapy.

Design, Synthesis, Docking Study, and Antiproliferative Evaluation of Novel Schiff Base–Benzimidazole Hybrids with VEGFR-2 Inhibitory Activity

A new series of Schiff-benzimidazole hybrids 3a-o has been designed and synthesized. The structure of the target compounds was proved by different spectroscopic and elemental analysis tools. The target compounds were evaluated for their in vitro cytotoxic activity against 60 cancer cell lines according to NCI single- and five-dose protocols. Consequently, four compounds were further examined against the most sensitive lung cancer A549 and NCI-H460 cell lines. Compounds 3e and 3g were the most active, achieving 3.58 ± 0.53, 1.71 ± 0.17 and 1.88 ± 0.35, 0.85 ± 0.24 against A549 and NCI-H460 cell lines, respectively. Moreover, they showed remarkable inhibitory activity on the VEGFR-2 TK with 86.23 and 89.89%, respectively, as compared with Sorafenib (88.17%). Moreover, cell cycle analysis of NCI-H460 cells treated with 3e and 3g showed cellular cycle arrest at both G1 and S phases (supported by caspases-9 study) with significant pro-apoptotic activity, as indicated by annexin V-FITC staining. The binding interactions of these compounds were confirmed through molecular docking studies; the most active compounds displayed complete overlay with, and a similar binding mode and pose to, Sorafenib, a reference VEGFR-2 inhibitor.