Synthesis or preparation, physicochemical characterization, and H460 cell inhibition of selenium nanoparticles stabilized by Marsdenia tenacissima residue polysaccharide.

As a common herbal medicine, Cuscuta chinensis Lam is widely used for cancer treatment in China. However, the anti-lung cancer effect of the bioactive constituents in C. chinensis and, the potential molecular mechanisms of action have yet to be elucidated. Bioassay-guided fractionation was used to isolate luteolin from the water extract of C. chinensis (CLW). The structure of luteolin was determined by spectroscopic analysis. The viability of A549 and H1650 lung cancer cells was determined using the MTT assay. Annexin V-FITC staining assay and cell cycle analysis were performed to explore the apoptosis and cell cycle phase distribution of lung cancer cells, respectively. Transwell invasion, wound healing, transwell migration, and adhesion assays were conducted to observe the lung cancer cell invasion, migration, and adhesion. Protein expression was determined via Western blot analysis. Luteolin was isolated from CLW by bioassay-guided fractionation, and its structure was determined by HR-ESI-MS and NMR. Luteolin inhibited the viability of A549 and H1650 lung cancer cells in a dose and time-dependent manner. Luteolin also dose-dependently induced apoptosis, and arrested the cell cycle at the G0/G1 phase in both cell types. Treatment with luteolin dose-dependently inhibited the invasion, migration, and adhesion of these cells. Luteolin consistently up-regulated FOSB, FGFBP1, and NPTX1 protein expression levels, and down-regulated H3K9me3, SETDB1, and MAP2K6 protein expression levels in A549 and H1650 cells. Co-treatment of luteolin and mithramycin A on A549 and H1650 lung cancer cells exhibited stronger up-regulation of FOSB and NPTX1 protein expression levels, and stronger down-regulation of SETDB1, H3K9me3, and MAP2K6 protein expression levels than luteolin or mithramycin A treatment alone. Co-treatment of luteolin and mithramycin A synergistically inhibited A549 and H1650 cell viability; induced apoptosis; delayed cell cycle at the G0/G1 phase; and inhibited the invasion, migration, and adhesion of A549 and H1650 cells compared with the treatment of luteolin or mithramycin A alone. Luteolin may suppresses the viability, invasion, migration, and adhesion of lung cancer cells via co-treatment with mithramycin A.

Background: Non-small-cell lung cancer (NSCLC) remains a major therapeutic challenge due to its high incidence and mortality. Herba Patriniae (HP), a traditional Chinese medicine, has long been used for respiratory disorders and exhibits anti-cancer potential. However, the therapeutic effects of HP on NSCLC and the underlying mechanisms have not been fully elucidated. Methods: Network pharmacology was applied to identify the core active components of HP and their potential targets in NSCLC. The anti-cancer effects of the core HP component Linarin on the malignant phenotypes of NSCLC cells were characterized using Tumor Protein P53 (p53) wild-type A549 and p53-null H1299 cell lines with Cell Counting Kit-8 (CCK-8), EdU fluorescence staining, colony formation, apoptosis analysis, cell cycle analysis, and senescence-associated β-galactosidase (SA-β-gal) staining, together with molecular docking and Western blotting analyses. Results: Network pharmacology analysis identified Linarin as the core active component of HP and screened out six hub targets, including Cyclin Dependent Kinase 1/4 (CDK1/4), Cyclin A2/B1 (CCNA2/B1), and Checkpoint Kinase 1/2 (CHEK1/2), which were found to be mainly enriched in cell cycle and senescence pathways. In vitro assays showed that Linarin dose-dependently (0-200 μM) inhibited NSCLC cell proliferation, induced G0/G1 phase arrest, and promoted cellular senescence and apoptosis in both cell lines, irrespective of p53 status. Molecular docking confirmed strong binding affinities between Linarin and the hub targets, and Western blotting confirmed that Linarin downregulated CCNA2/B1 and CHEK1. Conclusions: This study demonstrates that Linarin, the core active component of HP, exerts potent anti-NSCLC effects by inducing G0/G1 arrest, senescence, and apoptosis. These effects are associated with the downregulation of key cell cycle regulators, including CCNA2/B1 and CHEK1. Together, these findings highlight the potential of Linarin as a promising therapeutic option for NSCLC.

Non-small cell lung cancer (NSCLC) is among the most aggressive malignancies threatening human health. Histone deacetylase inhibitors (HDACi) have been shown to suppress epidermal growth factor receptor (EGFR) signaling, making them promising candidates for NSCLC therapy. This study aimed to evaluate the effects of Entinostat on NSCLC. The anti-proliferative effect of Entinostat was assessed using MTT assays, with four other HDAC inhibitors (the pan-HDAC inhibitor SAHA and selective HDAC inhibitors BRD73954, BG45, and NKL22) as controls. EGFR expression and phosphorylation of STAT3, AKT, and p38 were measured in vitro and in vivo via Western blot. Apoptosis was analyzed by flow cytometry, and expression of apoptosis regulators p53 and p21 was assessed by Western blot. The in vivo anti-tumor activity of Entinostat was evaluated using NSCLC xenograft models. Entinostat exhibited more potent anti-NSCLC activity than the other HDAC inhibitors in H460 and H1975 cell lines, with IC50 values of 0.69±0.03 μM and 0.20±0.01 μM, respectively. Western blot analysis demonstrated that Entinostat reduced EGFR expression and decreased phosphorylation of STAT3, AKT, and p38, indicating suppression of EGFR signaling both in vitro and in vivo. In xenograft models, treatment with 40 mg/kg Entinostat significantly inhibited tumor growth, though it also affected mouse body weight. Entinostat demonstrates strong anti-NSCLC activity by suppressing EGFR expression and downstream signaling, highlighting its potential as a therapeutic agent.

One new phenylethanoid glycoside, named bungaside A (1), along with six known phenylethanoid glycosides (2-7), were isolated from the dried aerial parts of Clerodendrum bungei Steud. Their structures were elucidated from extensive spectroscopic analysis and hydrolysis. All the isolates were evaluated for their anti-tumor effects against H460, A549, and HepG2 cancer cell lines. Compound 7 showed moderate activity against all cell lines, with the half-maximal inhibitory concentration (IC50) values ranging from 2.25 to 13.13 µM. Meanwhile, compounds 3 and 6 displayed weak activities on A549 with the IC50 values of 11.61 ± 1.38 and 16.68 ± 1.16 µM. Compounds 3 and 6 displayed moderate activities on H460 with the IC50 values of 5.10 ± 0.12 and 7.23 ± 0.65 µM, respectively. Besides, the preliminary structure-activities relationship showed that the skeleton of phenylethanoid glycosides containing a monosaccharide may have a stronger anticancer effect than their corresponding disaccharides, and the increase in the methylation of the hydroxyl group on the aromatic ring is also an important reason decrease in activity.

Background/Objectives: The enhancement of antitumor immune responses by radiotherapy (RT) is partially attributed to the activation of the IFN-type-I pathway. However, the loss of HLA-class-I molecules, which occurs in a large percentage of non-small-cell lung cancers (NSCLCs), may block the cytotoxic effect of T-cells and immunotherapy (IO). Moreover, autophagy is also involved in HLA downregulation. We investigated the complex interactions between RT, HLA molecules, autophagy, and IFN-type-I responses. Methods: The A549, H1299, and ATG7-deficient NSCLC cell lines, along with the modified shLC3A H1299 cell line, were used for in vitro experiments. The effect of RT (8 and 3 × 8 Gy) on Interferon beta (IFNβ), IFN-stimulated genes (ISGs), and HLA-class-I expression in combination with IFN-type-I-response inhibitors (Ruxolitinib, Tofacitinib, Amlexanox) targeting the JAK and TBK1 was studied with Flow cytometry and RT-PCR. Results: RT significantly induced HLA-class-I expression. A parallel upregulation of IFNβ and ISGs mRNA levels was also documented. Although the IFN-type-I-response inhibitors suppressed the RT-induced IFNβ and ISGs expression, their effect on HLA-class-I expression was minimal. Blockage of LC3A autophagy (shLC3A cell line) significantly upregulated HLA-class-I basal levels, and RT further enhanced HLA expression. IFN-type-I-response inhibitors blocked the RT-inductive effect in the shLC3A H1299, but had no effect in the ATG7-deficient H1650 cell line. Conclusions: The current study supports the theory that baseline autophagy, RT-induced autophagy blockage, and IFN-type-I response enhancement define the HLA-class-I levels in NSCLC cells. This complex interplay emerges as a promising target for the development of radio-vaccination strategies to enhance the efficacy of radio-immunotherapy.

Propolis from stingless bees is a natural resinous substance with diverse therapeutic properties, including anti-cancer activity. Despite increasing global interest, little is known about the bioactive potential of propolis from Southeast Asian stingless bees, particularly those native to Brunei Darussalam. Therefore, we investigated propolis extracts from five stingless bee species in Brunei and elucidated the underlying molecular mechanisms using transcriptomic and metabolomic profiling. Propolis extracts from Heterotrigona itama, Tetragonula melanoleuca, Tetrigona binghami, Geniotrigona thoracica, and Lepidotrigona canifrons were tested against lymphoma (U2932, HT, OCI-LY3), lung (H1975) and bladder (EJ) cancer cell lines. RNAseq and pathway enrichment analysis were performed to investigate the molecular mechanisms influenced by ethanol extracts from the three stingless bee species, H. itama, T. binghami, and T. melanoleuca on representative cell lines. Gas chromatography/mass spectrometer (GC-MS)-based metabolomics was performed for metabolite profiling of ethanol and ethyl acetate propolis extracts. Ethanol extracts elicited greater anticancer activity in general, as compared to ethyl acetate extracts. Ethanol propolis extracts from T. melanoleuca and H. itama were the most potent amongst the five stingless bee species, particularly on the lymphoma cell lines. Transcriptomic pathways involved in cell cycle progression, including E2F Targets and G2M Checkpoint, were downregulated in the EJ and H1975 cell lines, suggesting that the extracts may induce cell cycle arrest, particularly in adherent cells. MTORC1 signaling were downregulated across multiple cell lines. Interestingly, upregulation of several inflammation-related pathways, including TNFα signaling via NF-κB, Interferon Alpha Response, Interferon Gamma Response, and Inflammatory Response was observed. GC-MS analysis identified six major classes of compounds, including polyketides, phenolic acids and terpenoids, which were enriched in ethanol compared with ethyl acetate extracts. Propolis extracts from Brunei stingless bees demonstrate anti-cancer properties associated with pro-inflammatory and anti-oncogenic signalling activity. These findings support further investigation of their bioactive constituents as anti-cancer agents.

Lung cancer is a major cause of cancer-related deaths, and current therapies are often limited by poor selectivity, systemic toxicity, and resistance. The Wnt/β-catenin signaling pathway is central to lung cancer progression, with Traf2- and Nck-interacting kinase (TNIK) acting as a critical co-activator. To improve solubility, bioavailability, and tumor selectivity, we synthesized an N-glucoside derivative of the TNIK inhibitor KY-05009 (Compound 1). Compound 1 showed stronger cytotoxic activity than KY-05009 against A549, HCC827, and H1975 cell lines, with markedly lower IC₅₀ values, with no cytotoxicity to normal cell line. In HCC827 cells, it induced apoptosis, G2/M arrest, and mitochondrial depolarization in a dose-dependent manner, and also reduced migration and invasion. RT-PCR confirmed downregulation of Wnt target genes Axin2 and Survivin, consistent with inhibition of Wnt/β-catenin signaling. These results indicate that Compound 1 suppresses lung cancer cell growth and metastasis through multiple mechanisms and may serve as a promising lead for targeted therapy.

Lung cancer remains one of the leading causes of cancer-related mortality worldwide, with therapeutic efficacy often hindered by the development of multidrug resistance. Consequently, alternative strategies to slow down tumor progression warrant rigorous investigation. Bioactive molecules derived from tissues and organs have shown potential therapeutic properties for several diseases. We investigated the biological role of soluble bioactive factors derived from lyophilized porcine freeze-dried lung tissue (FDLT), as they may contain tumor-suppressing components involved in the progression of non-small cell lung cancer (NSCLC). NSCLC H1975 and PC9 cell lines were treated with FDLT at concentrations of 0.25 mg/mL and 0.5 mg/mL. Cell cycle analysis and mitochondrial membrane potential (MMP) assays were performed to assess cell proliferation and cell death activation. In parallel, epithelial–mesenchymal transition (EMT) markers were detected by qRT-PCR. Our findings showed that FDLT treatment reduced the viability of H1975 and PC9 cells in a dose-dependent manner, along with significant suppression of cell proliferation and colony formation. Moreover, FDLT treatment altered the cell cycle phases and determined a concomitant reduction of cyclin D1 levels as well as induction of mitochondria depolarization by suppressing MMP. Finally, qRT-PCR revealed significant downregulation of EMT-related genes vimentin and N-cadherin, along with the EMT transcription factor Twist. These findings highlight soluble FDLT-derived biomolecules as a potential tool to design alternative treatment strategies for NSCLC.

IntroductionCD26/dipeptidyl peptidase 4 (CD26, DPP4) is a transmembrane exopeptidase that modulates tumorigenesis in different malignancies. We demonstrated before that CD26 inhibition decreases lung tumor growth in experimental models. Here, we analyzed the prognostic significance of CD26 expression and its correlation with epithelial-to-mesenchymal transition (EMT) markers in a large series of patients with non-small cell lung cancer (NSCLC).Patients and methodsNSCLC samples from operated patients were analyzed using immunohistochemistry (IHC) for the expression of CD26 and EMT markers. CD26 was scored semi-quantitatively employing tissue microarrays. Lung cancer cell lines [H460, Lewis lung carcinoma (LLC)] were tested for EMT markers, and a colony formation assay was used to test the effect of treatment with the CD26 inhibitor vildagliptin.ResultsTumor samples from 904 patients with NSCLC were analyzed. CD26 IHC expression was significantly higher in adenocarcinoma compared to squamous cell carcinoma (p < 0.0001). Patients with adenocarcinoma and CD26 expression had a better overall survival than patients without CD26 expression. The lack of CD26 expression was shown to be an independent risk factor for worse survival. CD26-expressing adenocarcinomas showed a higher expression of Vimentin and Elastin (p = 0.0027 and p < 0.0001, respectively), while E-cadherin expression was lower in this group of patients (p = 0.0021). In vitro, treatment with vildagliptin reduced the expression of Vimentin and the capacity for colony formation in H460 and LLC cell lines.Summary and conclusionThe correlation of CD26 expression in lung adenocarcinomas and better patient survival, the antiproliferative effect on tumor cells by CD26 inhibition, and an altered EMT status give rise to the hypothesis that CD26 inhibitors impact the biology and clinical course of lung adenocarcinomas.

Following the publication of the above paper, it was drawn to the Editor's attention by a concerned reader that the Bcl‑2 protein bands shown for the HCC827 cell line in the western blots in Fig. 3A on p. 342 were unexpectedly similar to the Akt protein bands shown for the A549 cell line in Fig. 3B. In addition, the Bcl‑2 protein bands shown for the H358 and HCC827 cell lines (the left‑hand and middle gels) possibly contained a pair of mutually overlapping protein bands, and the β‑actin control bands featured in the left‑hand and middle lanes of Fig. 3A for the H358 and HCC827 cell lines, and the β‑actin control bands featured in the middle and right‑hand lanes for the H358 and HCC827 cell lines in Fig. 1C on p. 340, were similarly more similar than might have been expected. The authors were contacted by the Editorial Office to offer an explanation for this possible anomaly in the presentation of the data in this paper, although up to this time, no response from them has been forthcoming. Owing to the fact that the Editorial Office has been made aware of potential issues surrounding the scientific integrity of this paper, we are issuing an Expression of Concern to notify readers of this potential problem while the Editorial Office continues to investigate this matter further. [International Journal of Oncology 35: 337‑345, 2009; DOI: 10.3892/ijo_00000345].

Cyanine 5-huwentoxin-IV as a novel imaging probe to detect hNav1.7 channel overexpressed in non-small cell lung cancer.

Repurposing existing drugs offers a promising approach to cancer therapy. Fosinopril, an angiotensin converting enzyme inhibitor (ACEI) approved for hypertension, has demonstrated antitumor effects in hepatocellular carcinoma. However, its activity in non-small cell lung cancer (NSCLC) remains poorly understood. Here, we explore the potential anti-NSCLC effects of fosinopril in vitro and in vivo and its action mechanisms. The antiproliferative effects of fosinopril on NSCLC cells were assessed through the A549 and H1299 cell lines. Network pharmacology and proteomics were utilized to predict fosinopril’s molecular mechanisms in NSCLC. A subcutaneous xenograft model in nude mice was established to evaluate the in vivo anticancer effects and mechanisms of fosinopril. Fosinopril significantly inhibited the proliferation and colony formation of NSCLC cells. Additionally, fosinopril induced pyroptosis in NSCLC cells, evidenced by GSDME cleavage and increased LDH release. Mechanistically, fosinopril increased ROS levels, which activated Bax and downregulated mitochondrial membrane potential (MMP), resulting in Caspase-9 and Caspase-3 cleavage. Moreover, fosinopril suppressed tumor growth in a subcutaneous xenograft model and activated pyroptosis-related proteins. This study provides the first evidence that fosinopril inhibits NSCLC via GSDME-dependent pyroptosis, triggered by ROS-induced mitochondrial dysfunction and caspase activation. Further investigation into the detailed mechanisms of fosinopril’s anti-NSCLC activity is warranted.

Abstract Though Mica has been used for dysentery, bleeding and inflammation in Ayurveda medicine along with recent evidence on antimicrobial and antitumor effect, the underlying antitumor mechanism of Mica is not fully understood to date. Thus, the antitumor mechanism of processed Mica (PMC) was explored in non-small cell lung cancer cells. Herein PMC showed cytotoxicity and increased sub G1 population in H460 and A549 non-small cell lung cancer cells (NSCLCs). Also, PMC attenuated the expression of pro-PARP, pro-Caspase 3, cdk2, Cyclin A, NRF2, β-catenin, CCR4-NOT transcription complex subunit 2 (CNOT2), c-Myc and s-phase kinase-associated protein 2 (Skp2) compared to untreated control in H460 and A549 cells. Interestingly, CNOT2 was highly expressed at mRNA level in tumor tissues more than in normal tissues with poor prognosis in the patients with lung cancer. Also, TCGA reveals that CNOT2 closely interacts with c-Myc with spearman score of 0.28. Consistently, CNOT2 was bound to c-Myc in H460 cells by Immunoprecipitation and CNOT2 overexpression disturbed the ability of PMC to reduce c-Myc in A549 cells. Also, PMC significantly increased production of reactive oxygen species (ROS) in H460 and A549 cells. Conversely, ROS inhibitor, N-acetyl- l -cysteine (NAC), disturbed the capacity of PMC to reduce pro-PARP, pro-caspase 3, CNOT2 and c-Myc in A549 cells. Furthermore, PMC showed synergistic apoptotic potential with doxorubicin in H460 cells compared to doxorubicin alone by using CompuSyn analysis and SynergyFinder. Overall, these findings suggest that PMC induces apoptosis in lung cancers via inhibition of CNOT2/c-Myc and production of ROS with combinatorial potential with doxorubicin.

Evaluation of siramesine, β-Lapachone, and palbociclib as novel maintenance therapies after chemotherapy in small cell lung cancer.

Several first-, second-, and third-generation EGFR-TKIs have proven effective as anti-cancer therapeutics. However, the rapid development of drug resistance and mutations continues to be a major challenge in EGFR-TKI therapy. Addressing both intrinsic and acquired resistance resulting from EGFR mutations requires further exploration and the identification of novel inhibitors. In this study, we identified a new class of pyrido[2,3-b][1,4]oxazine-based inhibitors that exhibited potent EGFR kinase inhibitory activity. These compounds demonstrated significant anti-proliferative effects against EGFR-mutated non-small cell lung cancer (NSCLC) cell lines, including HCC827 (EGFR exon 19 deletion), H1975 (EGFR L858R/T790M double mutation), and A549 (wild-type EGFR overexpression). These novel pyrido[2,3-b][1,4]oxazine analogues were rationally designed and synthesized using the Suzuki cross-coupling reaction in a multi-step synthetic route. Anticancer evaluation of these derivatives using the MTT assay showed promising therapeutic potential. The most promising compounds were 7f, 7g, and 7h, with 7f showing potency (IC50 values: 0.09, 0.89, and 1.10 μM, in the HCC827, NCI-H1975 and A-549 cell lines, respectively) equivalent to clinically approved osimertinib. Interestingly, these compounds are selectively cytotoxic against cancer cells while not harming normal BEAS-2B cells at doses over 61 μM. Mechanistic studies demonstrated that compound 7f acts as an EGFR-TK autophosphorylation inhibitor, causing significant apoptosis (33.7% early and 9.1% late) compared to control conditions (2.4% early and 1.8% late). Molecular docking showed that the compounds scored similar to osimertinib, with the di-fluorophenyl group engaging the glycine-rich loop, pyridine substituents forming front pocket interactions, and essential hinge region interactions maintained, suggesting effective EGFR target engagement. These findings identify pyrido[2,3-b][1,4]oxazine derivatives as potential anticancer candidates worth further exploration for the development of targeted therapies against non-small cell lung cancer.

Lung adenocarcinoma (LUAD) is a prevalent subtype of nonsmall cell lung cancer with high mortality, underscoring the need for novel therapeutic strategies. Here, we demonstrated that the intravenous delivery of miR-502-3p via hollow mesoporous silica nanoparticles (HMSN; miR@HM-NH2) dramatically suppresses LUAD xenograft growth with negligible toxicity. MiR-502-3p is significantly downregulated in LUAD tissues and correlates with poor differentiation, metastasis, advanced TNM stage, and reduced overall survival, as shown by clinical samples and TCGA analysis. In vitro, miR-502-3p overexpression inhibited proliferation, migration, and invasion in LUAD cell lines, including PC9 and H1975 cells. Mechanistically, dual-luciferase assays and RNA-seq identified TPX2 as a direct target of miR-502-3p. miR-502-3p-mediated TPX2 inhibition downregulated phosphorylation of PI3K and AKT, with no reciprocal regulation on TPX2. Collectively, our findings reveal that the miR-502-3p/TPX2/PI3K/AKT axis plays a critical tumor-suppressive role in LUAD, with HMSN-based miR-502-3p delivery offering a promising therapeutic strategy.

Discovery of novel microtubule destabilizing agents via virtual screening methods and antitumor evaluation.

CUDC-907 exerts an inhibitory effect on non-small cell lung cancer associated with induction of mitotic catastrophe and downregulation of YAP/TAZ signaling.

Design, synthesis and evaluation of 1,2-dihydropyrido[2,3-d]pyrimidine-6‑carbonitrile derivatives as novel covalent inhibitors for the treatment of KRASG12C-mutant NSCLC.