Human Non-small Lung Cancer Research Articles

Overcoming drug-resistant tumors with selection gene drives

Drug resistance is a major hurdle prohibiting effective treatment of many diseases, including cancer. Using model-guided designs, Leighow etal.1 engineered a dual-switch selection gene drive system custom designed to combat drug-resistant tumors. By demonstrating remarkable killing efficacies in preclinical models using human non-small lung cancer cells invitro and in mice, this work describes an attractive mindset to develop next-generation anticancer therapies.

Activity-Based Nitric Oxide-Responsive Porphyrin for Site-Selective and Nascent Cancer Ablation.

Nitric oxide (NO) generated within the tumor microenvironment is an established driver of cancer progression and metastasis. Recent efforts have focused on leveraging this feature to target cancer through the development of diagnostic imaging agents and activatable chemotherapeutics. In this context, porphyrins represent an extraordinarily promising class of molecules, owing to their demonstrated use within both modalities. However, the remodeling of a standard porphyrin to afford a responsive chemical that can distinguish elevated NO from physiological levels has remained a significant research challenge. In this study, we employed a photoinduced electron transfer strategy to develop a panel of NO-activatable porphyrin photosensitizers (NOxPorfins) augmented with real-time fluorescence monitoring capabilities. The lead compound, NOxPorfin-1, features an o-phenylenediamine trigger that can effectively capture NO (via N2O3) to yield a triazole product that exhibits a 7.5-fold enhancement and a 70-fold turn-on response in the singlet oxygen quantum yield and fluorescence signal, respectively. Beyond demonstrating excellent in vitro responsiveness and selectivity toward NO, we showcase the potent photodynamic therapy (PDT) effect of NOxPorfin-1 in murine breast cancer and human non-small cellular lung cancer cells. Further, to highlight the in vivo efficacy, two key studies were executed. First, we utilized NOxPorfin-1 to ablate murine breast tumors in a site-selective manner without causing substantial collateral damage to healthy tissue. Second, we established a nascent human lung cancer model to demonstrate the unprecedented ability of NOxPorfin-1 to halt tumor growth and progression completely. The results of the latter study have tremendous implications for applying PDT to target metastatic lesions.

Design of novel analogues of t-DPH1 with reduced cytotoxicity, taking the three conserved characteristics of the dermaseptin family as the feasible starting point

In recent years, there has been growing scientific interest in balancing the bioactivity and cytotoxicity of antimicrobial peptides (AMPs) for more comprehensive research and application. In this study, we focused on t-DPH1, a representative member of the dermaseptin family, as a template. We synthesized five analogues were synthesised to to assess the impact of three conserved features of the dermaseptin family (1. the tryptophan residue at 3rd position, 2. the consensus motif at mid-region, and 3. C-terminal amidation) on the bioactivity of t-DPH1 and their potential to reduce cytotoxicity. Our results demonstrated that analogues lacking an amino group at the C-terminus, specifically t-DPH1-NH2, exhibited potent antimicrobial activity against Gram-negative bacteria, including Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae). Furthermore, t-DPH1-NH2 retained its robust antiproliferative activity against the human non-small lung cancer cell line H157. Regarding cytotoxicity, t-DPH1-NH2 displayed lower levels of haemolytic activity and cytotoxicity against two normal cell lines. Notably, we employed C. elegans as an in vivo model to assess the cytotoxicity of peptides, and the results revealed no induction of in vivo toxicity by t-DPH1-NH2. Collectively, t-DPH1-NH2 provides valuable insights for further investigation as promising bioactive peptide templates in the development of antibiotic and anticancer prototype drugs. The modifications implemented based on the conserved structure of the peptide family offer a new direction for reducing the cytotoxicity of peptides.

Cancer Stem Cell Formation Induced and Regulated by Extracellular ATP and Stanniocalcin-1 in Human Lung Cancer Cells and Tumors

Cancer stem cells (CSCs) are closely associated with metastasis and epithelial mesenchymal transition (EMT). We previously reported that extracellular ATP (eATP) induces and regulates EMT in cancer cells. We recently found that the gene stanniocalcin 1 (STC1) is significantly upregulated by eATP in human non-small lung cancer (NSCLC) A549 cells; however, the relationships among eATP, CSCs, and STC1 were largely unknown. In this study, we performed gene knockdown and knockout, and a wide variety of functional assays to determine if and how eATP and STC1 induce CSCs in NSCLC A549 and H1299 cells. Our data show that, in both cultured cells and tumors, eATP increased the number of CSCs in the cancer cell population and upregulated CSC-related genes and protein markers. STC1 deletion led to drastically slower cell and tumor growth, reduced intracellular ATP levels and CSC markers, and metabolically shifted STC1-deficient cells from an energetic state to a quiescent state. These findings indicate that eATP induces and regulates CSCs at transcriptional, translational, and metabolic levels, and these activities are mediated through STC1 via mitochondria-associated ATP synthesis. These novel findings offer insights into eATP-induced CSCs and identify new targets for inhibiting CSCs.

Abstract 888: Elucidating the mechanisms of eATP-induced changes in cell growth, energy metabolism, and cancer stem cells in human non-small lung cancer A549 cells

Abstract The tumor microenvironment (TME) has concentrations of extracellular ATP (eATP) 103-104 times higher than normal healthy tissues, implying that eATP may have important roles in tumor development and progression. Our previous study, cited by a Nature Reviews Cancer paper, showed that the extracellular ATP (eATP) is internalized by tumors via macropinocytosis, a type of endocytosis, to increase intracellular ATP (iATP) levels and support tumor cells growth, drug resistance, and cancer cell movement by initiating epithelial to mesenchymal transition (EMT). Recently, our lab found that eATP functions in promoting cancer cell growth, metastasis are similar to those of TGF-β, a well-known EMT and cancer stem cells (CSCs) inducer. Increasing reports state that the EMT and CSCs share some molecular links, but the detailed mechanisms and inductor of them are still far from clear. In this report, eATP’s function in CSCs induction was investigated first. Result shows that eATP treatment significantly induces the protein expression level of CSC related makers, increases cell colony numbers, and cell populations with CSC markers expressed in human lung cancer A549 cells. In addition, RNA-sequencing analysis reveals the gene Stanniocalcin 1 (STC1) is significantly upregulated in both eATP and TGF-β treatments. STC1 gene has been reported to be a competitive biomarker in the tracking of cancers’ progressing. Besides, STC1 exhibits concentration-dependent stimulation effects on electron transportation chain (ETC) and respiration. However, the detail function of STC1 gene in eATP induced cell growth is unknown. To find out the mechanism, CRISPR-Cas9 technique was used to generate STC1 gene targeted knockout (STC1 KO) A549 cells. STC1 KO cells show slower cell growth rate, lower intracellular ATP level and lower oxygen consumption rate (OCR) when compared with normal A549 cells in vitro. These results strongly indicate STC1 gene involved in eATP induced cell growth by alteration iATP level and metabolic profile. Overall, this study not only unravels new role of eATP in CSC induction, but also provides new mechanism of eATP induced cell growth by altering the protein expression level of STC1. Citation Format: Jingwen Song, Xiaozhuo Chen. Elucidating the mechanisms of eATP-induced changes in cell growth, energy metabolism, and cancer stem cells in human non-small lung cancer A549 cells [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 888.

P53-Related Anticancer Activities of Drimia calcarata Bulb Extracts Against Lung Cancer.

Current lung cancer treatment strategies are ineffective, and lung cancer cases continue to soar; thus, novel anticancer drugs and targets are needed, and medicinal plants are promising to offer better alternatives. This study was aimed at analysing two p53 splice variants during the potential anticancer activities of Drimia calcarata (Dc) methanol and water extracts against different human lung cancer cell lines of varying p53 mutation status, and these included mutant H1573 and mutant H1437 and p53-wild type (A549) cells. The anticancer activities of the Dc extracts were assessed by establishing the cytotoxic effect and the apoptosis-inducing capacity of these extracts, using the MTT assay and Annexin V analysis, respectively, with the latter confirmed using fluorescence microscopy. The molecular mechanisms induced by these extracts were further evaluated using cell cycle analysis and RT-PCR. Both extracts demonstrated safety against noncancerous lung MRC-5 fibroblasts and exhibited significant anticancer potency (p < 0.001) against the H1437 (IC50 values: 62.50μg/ml methanol extract and 125μg/ml WE), H1573 (IC50 value: 125μg/ml for both extracts) and A549 (IC50 value: 500μg/ml ME). The water extract had no effect on the viability of A549 cells. Treated H1437 cells underwent p53-dependent apoptosis and S-phase cell cycle arrest while H1573 treated cells underwent p53-independed apoptosis and G0/G1 cell cycle arrest through upregulation of p21 mRNA expression levels. The expression levels of STAT1, STAT3, STAT5A and STAT5B genes increased significantly (p < 0.001) following the treatment of H1573 cells with ME and WE. Treatment of H1437 cells with ME upregulated the STAT1, STAT3, STAT5A and STAT5B mRNAs. Our results indicate that the proliferative inhibitory effect of D. calcarata extracts on A549 and H1573 cells is correlated with the suppression of Bcl-2, STAT3 and STAT5B while that is not the case in H1437 cells. Thus, our results suggest that the dysregulation of anti-apoptotic molecules Bcl-2, STAT3, STAT5A and STAT5B in H1437 may play a role in cancer cell survival, which may consequently contribute to the development of p53-mutated non-small human lung cancer. Our results indicate that D. calcarata is a promising source of anticancer agents for the treatment of p53-mutant human non-small lung cancer cells than the p53-wild type human non-small lung cancer cells.

Screening of Apoptosis Pathway-Mediated Anti-Proliferative Activity of the Phytochemical Compound Furanodienone against Human Non-Small Lung Cancer A-549 Cells.

Furanodienone (FDN), a major bioactive component of sesquiterpenes produced from Rhizoma Curcumae, has been repeatedly acknowledged for its intrinsic anticancer efficacy against different types of cancer. In this study, we aimed to investigate the cytotoxic potential of furanodienone against human lung cancer (NSCLC A549) cells in vitro, as well as its underlying molecular mechanisms in the induction of apoptosis. Herein, we found that FDN significantly inhibited the proliferation of A549 cells in a dose-dependent manner. In addition, treatment with FDN potentially triggered apoptosis in A549 cells via not only disrupting the nuclear morphology, but by activating capsase-9 and caspase-3 with concomitant modulation of the pro- and antiapoptotic gene expression as well. Furthermore, FDN revealed its competence in inducing cell cycle arrest at G0/G1 phase in A549 cells, which was associated with decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), along with increased expression of CDK inhibitor p21Cip1. Intriguingly, FDN treatment efficiently downregulated the Wnt signaling pathway, which was correlated with increased apoptosis, as well as cell cycle arrest, in A549 cells. Collectively, FDN might represent a promising adjuvant therapy for the management of lung cancer.

Anti-Cancer and Anti-Inflammatory Activities of Three New Chromone Derivatives from the Marine-Derived Penicillium citrinum

Three new and uncommon chromone analogs, epiremisporine F (1), epiremisporine G (2), and epiremisporine H (3), were isolated from marine-origin Penicillium citrinum. Among the isolated compounds, compounds 2–3 remarkably suppressed fMLP-induced superoxide anion generation by human neutrophils, with IC50 values of 31.68 ± 2.53, and 33.52 ± 0.42 μM, respectively. Compound 3 exhibited cytotoxic activities against human colon carcinoma (HT-29) and non-small lung cancer cell (A549) with IC50 values of 21.17 ± 4.89 and 31.43 ± 3.01 μM, respectively, and Western blot assay confirmed that compound 3 obviously induced apoptosis of HT-29 cells, via Bcl-2, Bax, and caspase 3 signaling cascades.

Abstract 3106: Roles of extracellular ATP in inducing cancer stem cell (CSC)-like changes in non-small lung cancer cell line

Abstract Cancer is a major death-causing disease worldwide, and metastasis, a hallmark of cancer, is associated with up to 90% of all cancer-related deaths. Metastasis requires ATP, and the tumor microenvironment (TME) has much higher concentrations of intratumoral and extracellular ATP (eATP) than healthy tissue, implying that eATP may have potential roles in tumor development and progression. Our previous ATP studies, cited by a Nature Review Cancer paper in 20181 showed that eATP is internalized by cancer cell through macropinocytosis, and it promotes cancer cell growth, survival, and drug resistance. However, how intratumoral eATP plays roles in metastasis remains largely unclear. Our 2019 published results show that eATP promotes cancer migration and invasion, initiates epithelial to mesenchymal transition (EMT), alters expression level of EMT related protein markers such as ZEB1, SNAIL, SLUG in human non-small lung cancer cell (NSCLC) lines2. It has been reported that the EMT and cancer stem cells (CSCs) share some molecular links, but the detailed mechanisms involved are still unknown. Recently, we have found the eATP significantly induces the protein expression level of CSC related makers in A549 cells. We have also found that, after A549 cells were treated with 0.5mM and 0.75mM ATP for 6 and 24 hours, the ATP treated A549 cells were able to show significantly increased colony numbers by soft agar colony formation assay. Based on all these results, we hypothesize that extracellular ATP functions as a messenger, a signal facilitator, an energy molecule, and a transcription cofactor to induce CSC-like features to promote metastasis in NSCLC. RNAseq and metabolomics studies are being used to determine the transcriptional and metabolic changes associated with the ATP induced CSC process in NSCLC. The completion of the study will not only unravel eATP's roles in CSC induction and early steps of tumor metastasis, but also potentially provide novel promising therapeutic targets for inhibiting tumor metastasis.(1) Di Virgilio, F., Sarti, A. C., Falzoni, S., De Marchi, E., &amp; Adinolfi, E. (2018). Extracellular ATP and P2 purinergic signaling in the tumor microenvironment. Nature Reviews Cancer, 18(10), 601-618. (2) Cao, Y., Wang, X., Li, Y., Evers, M., Zhang, H., &amp; Chen, X. (2019). Extracellular and macropinocytosis internalized ATP work together to induce epithelial-mesenchymal transition and other early metastatic activities in lung cancer. Cancer Cell International, 19(1). Citation Format: Jingwen Song, Xiaozhuo Chen. Roles of extracellular ATP in inducing cancer stem cell (CSC)-like changes in non-small lung cancer cell line [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3106.

Malayoside, a cardenolide glycoside extracted from Antiaris toxicaria Lesch, induces apoptosis in human non-small lung cancer cells via MAPK-Nur77 signaling pathway

Lung cancer is the leading cause of cancer deaths in the world. Non-small cell lung cancer (NSCLC), with poor prognosis and resistance to chemoradiotherapy, is the most common histological type of lung cancer. Therefore, it is necessary to develop new and more effective treatment strategy for NSCLC. Nur77, an orphan member of the nuclear receptor superfamily, induces apoptosis in cancer cells including NSCLC cells, by high expression and translocation to mitochondria. Small molecules trigger expression and mitochondrial localization of Nur77 may be an ideal anti-cancer drug candidate. Here, we report malayoside, a cardiac glycoside in the extract of Antiaris toxicaria Lesch., had different sensitivities to NSCLC cells. Malayoside induced apoptosis in NCI-H460 cells. Meanwhile, malayoside induced Nur77 expression and mitochondrial localization, and its induction of apoptosis was Nur77-dependent. To investigate the molecular mechanism of malayoside inducing Nur77 and apoptosis, we found that malayoside activated MAPK signaling pathway, including both ERK and p38 phosphorylation. The suppression of MAPK signaling activation inhibited the expression of Nur77 and apoptosis induced by malayoside. Our studies in nude mice showed that malayside potently inhibited the growth of tumor cells in vivo. Furthermore, the anti-cancer effect of malayosidwas in vivo was also related to the elevated expression of Nur77, p-ERK, and p-p38 proteins. Our results suggest that malayoside possesses an anti-NSCLC activity in vitro and in vivo mainly via activation of MAPK-Nur77 signaling pathway, indicating that malayoside is a promising chemotherapeutic candidate for NSCLC.

ANXA8 Regulates Proliferation of Human Non-Small Lung Cancer Cells A549 via EGFR-AKT-mTOR Signaling Pathway

Annexin A8 (ANXA8) is a member of the annexin family, which had been reported to regulate multiple cancer cellular processes including proliferation, metastasis and inflammation. However, the specific role of ANXA8 in lung cancer cell biology remains unknown. Our previous transcriptome study revealed that ANXA8 mRNA was downregulated in curcumin analog (MHMD) -treated human non-small lung cancer cells (A549 cell line). Here, we continued to study the ANXA8 expression in A549 cells using reverse transcription-quantitative PCR and Western blotting, compared with that in human normal bronchial epithelium cells (BE-AS-2B cell line). Overexpression of ANXA8 via transfection of pEGFP-ANXA8 recombinant vector contributed to the proliferation and migration of A549 cells. Moreover, the cell cycle protein cyclin E1 was upregulated in ANXA8-transfected A549 cells. Knockdown of ANXA8 using an RNA interference technique decreased A549 cell viability and restrained their migration in vitro. The expression levels of multiple cellular factors, including EGFR, PI3K, Akt, mTOR, p70S6K and 4EBP1, in the epidermal growth factor receptor (EGFR) signaling pathway were also altered by ANXA8 knockdown or overexpression in A549 cells, which confirmed the activation of the EGFR/Akt/mTOR signaling pathway by ANXA8. The present results provided evidence to support further investigation of the functional identification of ANXA8 in lung cancer cells in the future.

Gold Nanoparticles: Synthesis and Effect on Viability of Human Non-Small Lung Cancer Cells

Gold nanoparticles recently showed great interest for many uses including food, drug and medical applications. The algae Undaria sp. well known as wakame in South Asia are considered to be large edible brown algae. It provides nutritious source of dietary fiber, vitamin Bs and mineral. The present study aimed to investigate the use of Undaria sp. for green synthesis of metallic gold nanoparticles. The synthesized nanoparticles were characterized for physicochemical properties including size measurement and tested in vitro for their effect on viability of human non-small lung cancer H-460 cell line using the MTT assay. From the results, brown algae were able to chemically form nanoparticles with chloroauric acid solution possibly due to the sulphated polysaccharides found in algae. The particle sizes were found to be approximately 10 nm. The gold nanoparticles stabilized by the algae could decrease the cancer cell viability. However, the properties and biological activity of nanoparticles seemed to depend upon reaction time and temperature. Conclusively, gold nanoparticles synthesized and stabilized by the algae could decrease the cancer cell viability, thus indicating the potential of such nanoparticles for further study for anticancer activity.

Paris saponin II-induced paraptosis-associated cell death increased the sensitivity of cisplatin

Paris Saponin II (PSII) has been regarded as an effective and imperative component isolated from Rhizoma Paridis saponins (RPS) and exhibited strong anti-tumor effects on a variety of cancer. Our results revealed that human non-small lung cancer cell lines NCI-H460 and NCI-H520 were exposed to 1 μM of PSII, which inhibited the proliferation of lung cancer cells and activated apoptosis, autophagy and paraptosis. PSII induced paraptosis-associated cell death prior to apoptosis and autophagy. It induced paraptosis based on ER stress through activation of the JNK pathway. Meanwhile, PSII increased the cytotoxicity of cisplatin through paraptosis-associated pathway. All in all, PSII induced paraptosis based on induction of non-apoptotic cell death, which would be a possible approach to suppress the multi-drug resistant to apoptosis.

Effects on Human Non-Small Lung Cancer Cell growth of Cu(II), Au(III) and Re(I) Complexes Containing N-donor Pyridyl Ligands: A Senior Undergraduate Research Project

Effects on Human Non-Small Lung Cancer Cell growth of Cu(II), Au(III) and Re(I) Complexes Containing N-donor Pyridyl Ligands: A Senior Undergraduate Research Project

Abstract 1542: Roles of extracellular ATP in inducing EMT and CSC-like changes to promote early steps of metastasis in non-small lung cancer cell lines

Abstract Cancer is a major death-causing disease worldwide, and metastasis, a hallmark of cancer, is associated with up to 90% of all cancer-related deaths. Metastasis requires ATP, and the tumor microenvironment (TME) has much higher concentrations of intratumoral and extracellular ATP (eATP) than healthy tissue, implying that eATP may have potential roles in tumor development and progression. Our previous ATP studies, cited by a Nature Review Cancer paper in 20181 showed that eATP is internalized by cancer cell through macropinocytosis, and it promotes cancer cell growth, survival, and drug resistance. However, how intratumoral eATP plays roles in metastasis remains largely unclear. Our 2019 published results show that eATP promotes cancer migration and invasion, initiates epithelial to mesenchymal transition (EMT), alters expression level of EMT related protein markers such as ZEB1, SNAIL, SLUG in human non-small lung cancer cell (NSCLC) lines2. It has been reported that the EMT and cancer stem cells (CSCs) share some molecular links, but the detailed mechanisms involved are still unknown. Recently, we have found the eATP significantly induces the gene expression level of CSC transcription factors (TFs): SOX2, NANOG and OCT4 in A549 cells in a time-dependent manner. We have also found that, after A549 cells were pretreated with 0.5mM for 6 hrs, the ATP-pretreated A549 cells were able to show significantly increased migration and invasion even in the absence of ATP addition. Based on all these results, we hypothesize that extracellular ATP functions as a messenger, a signal facilitator, an energy molecule, and a transcription cofactor to induce EMT and CSC-like features to promote metastasis in NSCLC. RNAseq and metabolomics studies are being used to determine the transcriptional and metabolic changes associated with the ATP induced EMT and CSC process in NSCLC. The completion of the project will not only unravel eATP's roles in EMT and CSC induction and early steps of tumor metastasis, but also potentially provide novel promising therapeutic targets for inhibiting tumor metastasis. Citation Format: Jingwen Song, Maria Evers, Xiaozhuo Chen. Roles of extracellular ATP in inducing EMT and CSC-like changes to promote early steps of metastasis in non-small lung cancer cell lines [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1542.

Extracellular synthesis of nanoselenium from fresh water bacteria Bacillus sp., and its validation of antibacterial and cytotoxic potential

Abstract In this present study, selenium reducing bacteria were isolated from fresh water pond. The cell free supernatant from B2 strain was found to effectively reduce sodium selenite and was identified as Bacillus sp. based on 16S r RNA sequencing. The selenium nanoparticles (Se NPs) synthesised using Bacillus sp. B2 were characterised by UV- spec, XRD, FTIR, FESEM and EDX. The selenium nanoparticles exhibited maximum peak at 280 nm in UV spectrophotometric analysis due to the surface plasmon resonance. FTIR analysis of cell free supernatant from Bacillus sp. B2 and synthesised selenium nanoparticles reveals that the proteins were mainly responsible for the reduction and stabilisation of Se nanoparticles. The XRD pattern shows the synthesised Se NPs were crystalline in nature with the average size of 33.2 nm. The SEM analysis reveals the Se NPs are spherical in shape with the size range of 20-50 nm and EDX pattern shows selenium exist as major element. The antibacterial activity of the Se NPs shows activity against all the tested bacteria. The lowest MIC and MBC of Se NPs was 8 μg/200 μL against Pseudomonas aeruginosa (NCIM 5031). The cytotoxicity of SeNPs against Human non-small lung cancer cell line A549 was tested by MTT assay that showed IC50 value of 3 μg/mL. The ET/AO staining of the Se NPs treated cells further revealed the result. Based on this we conclude that fresh water bacteria Bacillus sp. B2 can be used for selenium nanoparticles synthesis which is an ecofriendly and easy process for biomedical applications.

Synthesis and evaluation of moxifloxacin derivatives for effects on proliferation and apoptosis of NCI-H1299 cells

Eight novel moxifloxacin (MXF) derivatives 4a-h were synthesized by functional modification of the N-5-Aza ring. Their growth inhibitory activities on human non-small lung cancer cell NCI-H1299 and A549 were evaluated by the MTT colorimetric assay. Based on the half inhibitory concentration (IC50) values, we determined that compounds 4b was the most efficacious derivative (IC50 = 2.56 ± 0.07 μM for NCI-H1299 and IC50 = 13.69 ± 0.70 μM for A549, respectively) that inhibited the proliferation of NCI-H1299 cells. Of these, Compound 4b (1 – cyclopropyl – 6 – fluoro – 8 – methoxy – 4 – oxo – 7 – ((4aS,7aS) – 1 – (2 – oxo – 2 – (p – tolylamino) ethyl) hexahydro – 1H – pyrrolo [3,4-b] pyridine – 6(2H)-yl) – 1,4 – dihydroquinoline – 3-carboxylic acid) showed good potency against the growth of NCI-H1299 cells and also selectivity on HUVEC cells (IC50 > 500 μM). The dose-response relationship of the characteristic morphological changes of NCI-H1299 cells induced by Compound 4b was confirmed by AO/EB fluorescent staining. Furthermore, Compound 4b triggered apoptosis of NCI-H1299 in a concentration-dependent manner and arrested cells in the G0/G1 phase. These data indicate that the N-(p-tolyl)propanamide functionalized N-5-Aza ring of moxifloxacin may be a promising lead compound and candidate for the development of new agents against non-small-cell lung cancer.

Micellization, anti-proliferative activity and binding study of cationic gemini surfactants with calf thymus DNA

Aggregation behaviour of two cation gemini surfactants i.e., 1,3-bis (1-decylbenzimidazolium) propane bromide BG10 and 1,3-bis (1-octylbenzimidazolium) propane bromide BG8 was studied using conductivity and dynamic light scattering (DLS). The enthalpy (∆Hmо), entropy (∆Smо) and Gibbs free energy of micellization (∆Gmо) have been observed from the conductivity method at various temperatures. The anti-proliferative potential of these novel gemini surfactants against human non-small lung cancer cell line-H1299 has been investigated. Both gemini surfactants, BG8 and BG10 showed a considerable inhibition in cancer cell proliferation and IC50 values are observed to reduce with chain length. The ctDNA binding was also observed by UV–visible, transmission electron microscopy (TEM), ethidium bromide (EtBr) exclusion experiments, agarose gel electrophoresis, circular dichroism (CD) and viscometry techniques. These results were further validated by in-silico studies. The binding capability of BG surfactants to ctDNA can be observed from their ability to remove EtBr from the intercalating complex of DNA resulting in fluorescence quenching.

A Mesoporous Gd-MOF with Lewis Basic Sites for 5-Fu Delivery and Inhibition of Human Lung Cancer Cells In Vivo and In Vitro

A hydrolytically stable mesoporous Gd(III)-MOF {[Gd2(TATAB)2]·6 DMF}n (1) has been successfully prepared by reaction of Gd(NO3)3·6H2O with a flexible ligand 4,4′,4′′-s-triazine-1,3,5-triyltri-p-aminobenzoate (H3TATAB) under solvothermal conditions. Further, the nanostructure 1 could be obtained via an ultrasonic treatment method. Nitrogen adsorption measurements revealed the presence of mesoporosity as well as a moderate high BET surface areas in the activated nanostructure 1 (1a), which was further used in the 5-Fu loading with the uptake capacity of 47 wt%. Meanwhile, the controlled release of 5-Fu in a simulated human body with liquid phosphate-buffered saline solution was realized. In the biological study, the anti-proliferation activity of 5-Fu@1a on A549 human non-small lung cancer (NSCLC) cells after 5-Fu@1a exposure was evaluated by the CCK-8 preformation. The effect of 5-Fu@1a on A549 NSCLC cell migration and invasion ability was detected by transwell assay. The mechanism was revealed by the detection of the NLRP3 inflammasome activation level in A549 through western blot and ELISA assay. For further explore the inhibitory effect of 5-Fu@1a, the anti-tumor ability was evaluated in the in vivo xenograft model.

Nannochloropsis Extract-Mediated Synthesis of Biogenic Silver Nanoparticles, Characterization and In Vitro Assessment of Antimicrobial, Antioxidant and Cytotoxic Activities.

Objective:To investigate the biogenic synthesis of silver nanoparticles (AgNPs) using partially purified ethyl acetate extract of Nannochloropsis sp. hexane (EAENH) fraction of microalga. Methods:The green synthesis of AgNPs was confirmed with UV-Vis spectrum which shows the surface plasmon resonance (SPR) at 421 nm. Fourier Transform Infrared Spectra (FTIR) presented the involvement of functional groups like carboxyl groups of fatty acids, tetraterpenoids of xanthophylls, hydroxyl groups of polyphenols, carbonyl and amide linkage of proteins in the AgNP synthesis. Gas Chromatography-Mass Spectrometry analysis (GCMS) revealed that phytochemicals like octadecanoic acid and hexadecanoic acid imply in capping, bioreduction, and stabilization of AgNps.Result:High-resolution Transmission electron microscope (HRTEM), Dynamic light scattering (DLS), X-ray diffraction (XRD) and EDX analysis showed the crystalline form of the AgNPs with Z-average size 57.25 nm. The zeta potential value of -25.7 mV demonstrated the negative surface charge and colloidal stability of AgNPs. The antimicrobial activity of AgNPs displayed effective inhibition zone against selected bacterial and fungal pathogens. In vitro, antioxidant effects were assessed by 1,1-diphenyl-2-picryl-hydrazyl (DPPH), hydrogen peroxide and reducing power assays which revealed excellent scavenging potential for AgNPs than the extracts. The anti-proliferative potential of biofabricated AgNPs and extracts on Human Non-small lung cancer cell line (A549) was assessed using 3–(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay with IC50 values of 15 µgmL-1 and 175 µgmL-1 respectively. Conclusion:The study reveals that the microalgae-mediated AgNPs possesses potent antimicrobial and antioxidant activity along with the ability to stimulate apoptosis in A-549 cell line.