Anti-lung Cancer Activity Research Articles

Immunomodulatory Protein from Nectria haematococca Induces Apoptosis in Lung Cancer Cells via the P53 Pathway.

Our previous research has shown that a fungal immunomodulatory protein from Nectria haematococca (FIP-nha) possesses a wide spectrum of anti-tumor activities, and FIP-nha induced A549 apoptosis by negatively regulating the PI3K/Akt signaling pathway based on comparative quantitative proteomics. This study further confirmed that the anti-lung cancer activity of FIP-nha was significantly stronger than that of the reported LZ-8 and FIP-fve. Subsequently, 1H NMR-based metabolomics was applied to comprehensively investigate the underlying mechanism, and a clear separation of FIP-nha-treated and untreated groups was achieved using pattern recognition analysis. Four potential pathways associated with the anti-tumor effect of FIP-nha on A549 cells were identified, and these were mainly involved in glycolysis, taurine and hypotaurine metabolism, fructose and mannose metabolism, and glycerolipid metabolism. Metabolic pathway analysis demonstrated that FIP-nha could induce A549 cell apoptosis partly by regulating the p53 inhibition pathway, which then disrupted the Warburg effect, as well as through other metabolic pathways. Using RT-PCR analysis, FIP-nha-induced apoptosis was confirmed to occur through upregulation of p53 expression. This work highlights the possible use of FIP-nha as a therapeutic adjuvant for lung cancer treatment.

RETRACTED: Two polyoxometalate-based coordination polymers: Synthesis, characterization and in vitro anti-lung cancer activity

This article has been retracted, and the online PDF has been watermarked “RETRACTION”. The retraction notice is available at http://doi.org/10.3233/MGC-220954.

The effects and mechanisms of a biosynthetic ginsenoside 3β,12β-Di-O-Glc-PPD on non-small cell lung cancer.

BackgroundA biosynthetic ginsenoside, 3-O-β-D-glucopyranosyl-12-O-β-D-glucopyranosyl-dammar-24-ene-3β, 12β, 20S-triol (C3C12PPD), showed antitumor activity against many tumor cells in vitro, especially had better anti-lung cancer activity than Rg3 in vitro and in vivo. However, the effects and molecular mechanisms of C3C12PPD on non-small cell lung cancer (NSCLC) remain unclear. According to previous studies, we hypothesized ginsenoside C3C12PPD could inhibit the tumor growth of NSCLC by targeting proliferation, migration and angiogenesis.MethodsA thiazolyl blue tetrazolium bromide assay (MTT) was performed to evaluate cell viability. Additionally, Transwell and tube formation assays were conducted to analyze cell migration and angiogenesis. The Lewis and A549 tumor xenograft experiments were also performed to investigate the effects of C3C12PPD on tumor growth in vivo, Western blotting and IHC assay were performed to analyze protein expression.ResultsC3C12PPD could effectively inhibit the proliferation and migration of lung cancer cells, and tube formation of EA.hy926 cell. Ginsenoside C3C12PPD suppressed Lewis and A549 tumor growth in vivo without obvious side effects on body weight and the hematology index. In addition, the Western blot analysis revealed that the effects of C3C12PPD on lung cancer were mediated by inhibiting Raf/MEK/ERK, AKT/mTOR and AKT/GSK-3β/β-Catenin signaling pathways. Finally, C3C12PPD could significantly inhibit the proliferation index and vessel number in Lewis xenograft tumors analyzed by IHC.ConclusionThe results of the present study suggest that ginsenoside C3C12PPD may serve as a potential therapeutic candidate compound against NSCLC.

Anti-lung cancer activity of Schizonepetae Spica extract and identification of its compounds by ultra-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry

Schizonepetae Spica (SS), a well-known traditional Chinese medicine has been widely used over thousands of years. In modern medicine, it has been adopted in the traditional prescription for cancer in clinic. In order to further develop the medicinal value of SS, we conducted cell viability assay and cell apoptosis research and proved that the extraction of Schizonepetae Spica (SSE) possesses prominent pharmacological activity against lung tumor. It can promote the late apoptosis of A549 cells. And the growth inhibition of SSE on A549 cells was manifested in a concentration-and time-dependent manner. Furthermore, an UPLC-QTOF-MS method was applied to identify the chemical components of SSE for the first time. A total of 30 compounds were tentatively identified, of which flavonoids and organic acids are the main ingredients. The results presented here would be helpful for the further study of plasma migration components and quality control of SS, which lay a foundation for the discovery of the pharmacodynamic basis of SSE and the development of new anti-tumor drugs.

Discovery of human lactate dehydrogenase 5 inhibitors (hLDH5) with anti-lung cancer activity through an in silico method and biological validation.

Human lactate dehydrogenase 5 (hLDH5) is an important metabolic enzyme playing critical roles in the anaerobic glycolysis. Herein, we employed an in silico method and biological validation to identify a novel hLDH5 inhibitor with a promising cellular activity under hypoxia condition. The identified compound 9 bound to hLDH5 with a Kd value of 1.02 µM, and inhibited the enzyme with an EC50 value of 0.7 µM. Compound 9 exhibited a weak potency against NCI-H1975 cell proliferation under normal condition (IC50 = 36.5 µM), while dramatically increased to 5.7 µM under hypoxia condition. In line with the observation, hLDH5 expression in NCI-H1975 cell under hypoxia condition is much higher as compared to the normal oxygenated condition, indicating the hLDH5 inhibition may contribute to the cancer cell death.

Toward Rational Design of Novel Anti-Cancer Drugs Based on Targeting, Solubility, and Bioavailability Exemplified by 1,3,4-Thiadiazole Derivatives Synthesized Under Solvent-Free Conditions.

The 1,3,4-thiadiazole derivatives (9a–i) were synthesized under solvent free conditions and their chemical composition was confirmed using different spectral tools (IR, Mass, and NMR spectrometry). All the synthesized compounds were screened for their anti-cancer potentiality over human breast carcinoma (MCF-7) and human lung carcinoma (A-549). Most of the tested compounds showed remarkable anti-breast cancer activity. However, compound 4 showed the most anti-lung cancer activity. Then, compounds with cytotoxic activity ≥ 80% over breast and lung cells were subjected to investigate their specificity on human normal skin cell line (BJ-1). Compounds 9b and 9g were chosen owing to their high breast anti-cancer efficacy and their safety, in order to study the possible anti-cancer mode of action. Otherwise, drug delivery provides a means to overcome the low solubility, un-targeted release, and limited bioavailability of the prepared 1,3,4-thiadiazole drug-like substances. Compounds 9b and 9g were chosen to be encapsulated in Na-alginate microspheres. The release profile and mechanism of both compounds were investigated, and the results revealed that the release profiles of both microspheres showed a sustained release, and the release mechanism was controlled by Fickian diffusion. Accordingly, these compounds are promising for their use in chemotherapy for cancer treatment, and their hydrophilicity was improved by polymer encapsulation to become more effective in their pharmaceutical application.

The ginsenoside Rk3 exerts anti-esophageal cancer activity in vitro and in vivo by mediating apoptosis and autophagy through regulation of the PI3K/Akt/mTOR pathway.

The rare ginsenoside Rk3 is a bioactive component derived from ginseng and Panax notoginseng that has been proven to possess anti-lung cancer activity. However, the effect of Rk3 on human esophageal cancer has not yet been reported. In this study, we aimed to explore its anticancer curative effect and potential molecular mechanisms in the Eca109 and KYSE150 cell lines. We found that Rk3 was able to significantly repress cell proliferation and colony formation in both Eca109 and KYSE150 cells in vitro. In the KYSE150 xenograft model, Rk3 obviously inhibited tumor growth and exhibited little toxicity in organs. Moreover, Rk3 could trigger G1 phase arrest and induce apoptosis and autophagy. Interestingly, apoptosis induced by Rk3 could be partly abrogated by 3-MA (an autophagy inhibitor), implying that autophagy could enhance apoptosis. Further studies indicated that pretreatment with the Akt inhibitor GSK690693 or the mTOR inhibitor rapamycin promoted Rk3-induced apoptosis and autophagy, demonstrating that the PI3K/Akt/mTOR pathway is related to Rk3-induced apoptosis and autophagy. In conclusion, the present study is the first to clarify that Rk3 can inhibit Eca109 and KYSE150 cell proliferation through activating apoptosis and autophagy by blocking the PI3K/Akt/mTOR pathway, suggesting that Rk3 may be a promising antitumor agent for esophageal cancer. In addition, this study provides ideas and an experimental basis for further research on the anti-esophageal cancer effects of the ginsenoside Rk3 and its mechanism.

Synthesis and Anti Lung Cancer Activity of 3-Arylspiro[oxirane-2,3'- thiochroman]-4'-one Derivatives

A series of 3-arylspiro[oxirane-2,3'-thiochroman]-4'-one derivatives were synthesized and characterized by spectroscopy like 1H NMR, 13C NMR, mass spectrometry and elemental analysis. They were evaluated for their anti-lung cancer activity on human lung cancer cell line A-549 in DMSO. Compounds under study were found to be potent anti-lung cancer agents with GI50 values less than 10 with respect to positive control adriamycin.

9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer.

Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC.

Multifunctional Applications of Microwave-Assisted Biogenic TiO2 Nanoparticles

TiO2 nanoparticles were prepared by a microwave-assisted green method using Andrographis paniculata as fuel. XRD, Raman, FESEM with EDS, TEM and UV-DRS have been used for characterization of TiO2 nanoparticles. XRD exhibits a tetragonal structure with the average crystallite size of 19 nm. From Raman studies, the peaks at 196 (Eg), 395 (B1g), 514 (A1g) and 639 (Eg) are revealing the anatase phase of TiO2. FESEM and TEM images confirm the nanoparticles with average particle size are 25 nm. Optical bandgap of biogenic TiO2 nanoparticles is 3.27 eV. Photoluminescence spectrum of TiO2 nanoparticles showed blue and green emissions. The photocatalytic degradation study of biogenic TiO2 nanoparticles was investigated against the Rose Bengal (RB) dye under UV light irradiation. Microwave-assisted green synthesized TiO2 nanoparticles showed an excellent photocatalytic activity (RB dye). Antibacterial activity (disc diffusion method) of microwave-assisted biogenic TiO2 nanoparticles is studied against foodborne pathogens. TiO2 exhibits anti-lung cancer (human lung cancer A549: IC50: 24.96 µg/mL) activity along with biocompatibility.

A new Pb(II)-based coordination polymer constructed from a semirigid tricarboxylate ligand: crystal structure and anti-lung cancer activity

Abstract Based on a semirigid tricarboxylate ligand 5-((4-carboxyphenoxy)methyl)benzene-1,3-dioic acid (H3L), a new Pb(II)-based coordination polymer formulated as [Pb(HL)(H2O)](H2O) (1) was synthesized under solvothermal conditions and characterized by single-crystal X-ray structural analysis, power X-ray diffraction, and elemental analysis. Compound 1 is a two-dimensional layered structure formed by the connection of the one-dimensional Pb(II)-based secondary building unit chains with the partly deprotonated HL ligands, which are further extended into three-dimensional supermolecular structures through the H-bonds. Furthermore, the size of the as-prepared 1 could be downsized into the nano region through a simple ultrasonic method. Finally, the antilung cancer activities of 1 and the nanosized 1 have been probed via the MTT assay against three human lung cancer cell lines (A549, H1299, and PC9).

Antioxidant, Anti-Lung Cancer, and Anti-Bacterial Activities of Toxicodendron vernicifluum.

This work tested antioxidant, anti-lung cancer, and antibacterial activities by in vitro, in vivo, and computational experiments for the metabolites extracted from the bark, seed, and stem of Toxicodendron vernicifluum. The results showed that all the extracts significantly scavenged 1,2-diphenyl-1-picrylhydrazyl (DPPH) in a dose-dependent manner. But, the total phenol content (TPC) ranged from 2.12 to 89.25% and total flavonoids content (TFC) ranged from 1.02 to 15.62% in the extracts. The methanolic bark extract (MBE) exhibited higher DPPH scavenging activity than the other extracts, probably due to the higher content of the TPC and TFC present in it. Among the extracts, only the MBE showed anti-lung cancer activity at an acceptable level with a therapeutic index value (22.26) against human lung carcinoma. This was due to the cancer cell death in A549 induced by MBE through reactive oxygen species (ROS) generation, apoptosis, and cell arrest in G1 phase and inhibition of anti-pro-apoptotic protein survivin. Among the extracts, MBE showed significantly higher antibacterial activity as evident through the higher zone of inhibition 13 ± 0.5 mm against methycilin resistant strain of Staphylococcus aureus (MRSA), Salmonila enteria subp. enterica, and P. aeruginosa, 11 ± 0.3 mm against E. coli and 10 ± 0.2 mm against B. cereus. The MBE also showed an excellent antibacterial activity with lower minimal inhibitory concentration (MIC). Particularly, the MBE showed more significant antibacterial activity in MRSA. The in vivo antibacterial activity of the MBE was further tested in C. elegans model. The treatment of the MRSA induced cell disruption, damage and increased mortality of C. elegans as compared to the untreated and MBE treated C. elegans with normal OP50 diet. Moreover, the MBE treatment enhanced the survival of the MRSA infected C. elegans. The compounds, such as 2,3,3-trimethyl-Octane and benzoic from the MBE, metabolized the novel bacterial topoisomerases inhibitor (NBTI) and MRSA related protein (PBP2a). Overall the T. vernicifluum is potentially bioactive as evident by antioxidant, anti-lung cancer, and antibacterial assays. Further studies were targeted on the purification of the novel compounds for the clinical evaluation.

Tetracenomycin X Exerts Antitumour Activity in Lung Cancer Cells through the Downregulation of Cyclin D1.

Tetracenomycin X (Tcm X) has been reported to have antitumour activity in various cancers, but there have not been any studies on its activity with respect to lung cancer to date. Therefore, this study aims to investigate the anti-lung cancer activity of Tcm X. In this study, we found that tetracenomycin X showed antitumour activity in vivo and selectively inhibited the proliferation of lung cancer cells without influencing lung fibroblasts. In addition, apoptosis and autophagy did not contribute to the antitumour activity. Tetracenomycin X exerts antitumour activity through cell cycle arrest induced by the downregulation of cyclin D1. To explore the specific mechanism, we found that tetracenomycin X directly induced cyclin D1 proteasomal degradation and indirectly downregulated cyclin D1 via the activation of p38 and c-JUN proteins. All these findings were explored for the first time, which indicated that tetracenomycin X may be a powerful antimitotic class of anticancer drug candidates for the treatment of lung cancer in the future.

In Silico Analysis of the Betuline from the Fiddler Crab, Uca annulipes and its antimicrobial as well as anti lung cancer activities

Introduction: In silico analysis of the bioactive compound betuline from the fiddler crab, Uca annulipes and its antimicrobial activities were studied. The fiddler crabs, Uca annulipes were collected from Muttukadu Estuary located on the Kanchipuram District, Tamil Nadu, India, 35 K.M away from Chennai, on the East Coast Road route to Kovalam. Materials and Methods: Fiddler crabs were collected by hand picking method. From the muscle mass of the Crab the bioactive compound was isolated by GC-MS analysis. Molecular docking was performed to identify the protein ligand responsible for the affinity with lung cancer causing tumour cells. Results and Discussion: Hence betuline is the potential lead molecule for the inhibition of lung cancer protein and the most important residues for potential drug target as carbon hydrogen bond, conventional hydrogen bond and Vander Waals interaction. In vitro studies of antimicrobial activities clearly indicated that the different concentrations of betuline bioactive compound have the potential to control the bacteria such as Escherichia coli and Pseudomonas aeruginosa. In vitro studies of anticancer activities also evidently showed the different concentrations of bioactive compound betuline have the potential to control the proliferation of lung cancer cells. Conclusion: Reports are very scanty on this species studied and the reports are very old and hence this present investigation would give latest information on the isolation of bioactive compound for the production of pharmaceutical drugs against the lung cancer. These results will be decisive factor for determining a lead bioactive compound for further drug discovery process for the lung cancer.

Novel α-ketoamide based diazeniumdiolates as hydrogen peroxide responsive nitric oxide donors with anti-lung cancer activity.

A novel type of hydrogen peroxide (H2O2)-activated diazeniumdiolate based on an α-ketoamide moietey was developed as a nitric oxide (NO) donor. KA-NO-4 inhibited lung cancer cells with submicromolar activity. The H2O2-responsive behaviour of KA-NO-4 was thoroughly investigated. The NO-centered mechanism of action of KA-NO-4 was intracellularly studied.

Synthesis, activity evaluation, and pro-apoptotic properties of novel 1,2,4-triazol-3-amine derivatives as potent anti-lung cancer agents

In this study, a series of 4,5-bis(substituted phenyl)-4H-1,2,4-triazol-3-amine compounds was designed, synthesised, and evaluated to determine their potential as anti-lung cancer agents. According to the results of screening of lung cancer cell lines A549, NCI-H460, and NCI-H23 in vitro, most of the synthesised compounds have potent cytotoxic activities with IC50 values ranging from 1.02 to 48.01 µM. Particularly, compound 4,5-bis(4-chlorophenyl)-4H-1,2,4-triazol-3-amine (BCTA) was the most potent anti-cancer agent, with IC50 values of 1.09, 2.01, and 3.28 µM against A549, NCI-H460, and NCI-H23 cells, respectively, meaning many-fold stronger anti-lung cancer activity than that of the chemotherapeutic agent 5-fluorouracil. We also explored the effects of BCTA on apoptosis in lung cancer cells by flow cytometry and western blotting. Our results indicated that BCTA induced apoptosis by upregulating proteins BAX, caspase 3, and PARP. Thus, the potential application of compound BCTA as a drug should be further examined.

Anti-lung cancer activity and inhibitory mechanisms of a novel Calothrixin A derivative

AimsCAA45 is a calothrixin A (CAA) analogue with anti-cancer activity at nanomolar concentration. This study aimed to investigate the anti-lung cancer activity of CAA45 and explore its mechanisms of actions. Main methodsCAA and CAA45 were synthesized and their inhibition on DNA topoisomerase I (Topo I) performed by evaluating the relaxation of supercoiled pBR322 plasmid DNA and their anti-lung cancer capacity determined by cytotoxic assays, cell migration, cell cycle, cell apoptosis, cell autophagy and related signaling proteins expression by western blot. Key findingsCAA45 significantly inhibited human non-small cancer cell A549 and NCI-H1650 cells growth with IC50 values of 110 and 230 nM, respectively. In the A549 xenograft models, CAA45 displayed strong antitumor activities at a dose of 10 mg/kg. CAA45 inhibited Topo I activity and caused the cell cycle arrest at S phase, which also reduced A549 cell migration by inhibiting MMP-2 and MMP-9 expressions. Furthermore, CAA45 induced A549 cell apoptosis and autophagy. The apoptosis pathway was involved in the release of cytochrome c and caspase activation. CAA45 also inhibited Akt, activated JNK and up-regulated p53 signals in A549 cells, which may serve as a modulator to induce apoptosis and autophagy in cancer cells. SignificanceCAA45 exerted its anti-lung cancer effect via inhibition of Topo I, resulting in cell cycle arrest and cell migration, induction of mitochondria mediated cell apoptosis and autophagy via PI3K/Akt/JNK/p53 pathway. All these observations suggested that CAA45 could be a promising lead for anti-cancer drug discovery.

Design, Synthesis and Cytotoxic Evaluation of 4-Anilinoquinazoline– triazole–AZT Hybrids as Anticancer Agents

A series of 4-anilinoquinazoline–triazole–AZT hybrids were designed and synthesized as anticancer agents. Their cytotoxic potential has been evaluated by means of a micro-dilution assay against three human cancer cell lines (KB, epidermoid carcinoma; HepG2, hepatoma carcinoma; SK-Lu-1, non-small lung cancer). The biological results revealed that compounds 4b and 6d showed good anticancer activities against KB, HepG2, and Lu cell lines (IC50 values ranging from 9 μM to 100 μM). Especially, compounds 4b and 6d exhibited up to 3-fold more potent than reference drugs erlotinib hydrochloride and AZT in term of anti-lung cancer activity.

RETRACTED: Mixed-ligand strategy affording two new metal-organic frameworks: Photocatalytic, luminescent and anti-lung cancer properties

Abstract Mixed-ligand strategy afforded two new metal-organic frameworks (MOFs), namely [Ni(L)0.5(4,4′-bipy)0.5(H2O)2]n (1) and [Zn2(L)(bpp)2]n (2) (H4L = 1,3-di(3′,5′-dicarboxylphenyl)benzene, 4,4′-bipy = 4,4′–bipyridine and bpp = 1,3-di(4-pyridyl)propane), which were further characterized by elemental analyses, powder X-ray diffraction analyses and single crystal X-ray diffraction analyses. Compound 1 features a 4-fold interpenetrated 3D framework with (3,4)-connected dmd-type topology, and compound 2 features a 3D complicated framework with 4-connected topology. Moreover, the photocatalytic activity of compound 1 for the degradation of methyl blue (MB) and luminescent property of compound 2 were investigated in detail. In addition, the anti-lung cancer activities of both complexes have been evaluated via the MTT assay against three human lung cancer cells A549, H1299 and PC9.

Anti-lung Cancer and Anti-angiogenic Activities of New Designed Boronated Phenylalanine Metal Complexes.

Drug design and discovery studies still remain of great importance in the search for more convenient chemotherapeutic to avoid the drug resistance, systemic toxicity or the longterm side effects. A series of mononuclear gold (III) and platinum (II) complexes based on 4-dihydroxyboryl- DL-phenylalanine (BPA) was designed and synthesized, for the first time, by using 2, 2'-dipyridyl (L1) and 4, 4'-diaminobibenzyl (L2) ligands. Characterization of the synthesized complexes was achieved by using 1H-NMR, IR, MS and elemental analyses. MTT cell viability, endothelial tube formation, cancer cell colony formation and TRITCphalloidin cytoskeleton staining assays were performed on human umbilical vein endothelial (HUVEC) and human lung adenocarcinoma (A549) cells to establish the anticancer and anti-angiogenic activities of the complexes. It was determined that the organometallic complexes that include 2, 2'-dipyridyl ligand have higher antiproliferative activity than L2-based complexes in the micromolar range. Colony formation experiments showed that the anchorage-independent growth ability of A549s was significantly affected by the complexes in a concentration-dependent manner though L1-based complexes were more effective than L2-based ones. It was also clearly observed that the complexes have significant anti-angiogenic and cytoskeleton alterative activities. Consequently, the phenylalanine-based organometallic complexes seem to have anti-lung cancer and anti-angiogenic activities depending on the ligand type and a great potential in oncology drug development because phenylalanine amino acid has an ability to cross the cell membrane by using L-amino acid transport system. Design, synthesis and activity studies with amino acid analogs should be therefore increased to discover more efficient drugs to cure cancer diseases.