Agent For Treatment Of Lung Cancer Research Articles

Characterization, biological activity, and anticancer effect of green-synthesized gold nanoparticles using Nasturtium officinale L.

BackgroundNanostructured materials used have unique properties and many uses in nanotechnology. The most striking of these is using herbal compounds for the green synthesis of nanoparticles. Among the nanoparticle types used for green synthesis, gold nanoparticles (AuNPs) are used for cancer therapy due to their stable structure and non-cytotoxic. Lung cancer is the most common and most dangerous cancer worldwide in terms of survival and prognosis. In this study, Nasturtium officinale (L.) extract (NO), which contains biomolecules with antioxidant and anticancer effects, was used to biosynthesize AuNPs, and after their characterization, the effect of the green-synthesized AuNPs against lung cancer was evaluated in vitro.MethodsUltraviolet‒visible (UV‒Vis) spectrophotometry, scanning electron microscopy (SEM), transmission electron microscopy (TEM), energy dispersive X-ray spectroscopy (EDS), multiple analysis platform (MAP), and Fourier transform infrared (FT-IR) spectroscopy analyses were performed to characterize the AuNPs prepared from the N. officinale plant extract. Moreover, the antioxidant activity, total phenolic and flavonoid contents and DNA interactions were examined. Additionally, A549 lung cancer cells were treated with 2–48 µg/mL Nasturtium officinale gold nanoparticles (NOAuNPs) for 24 and 48 h to determine the effects on cell viability. The toxicity of the synthesized NOAuNPs to lung cancer cells was determined by the 3-(4,5-dimethylthiazol-2-il)-2,5-diphenyltetrazolium bromide (MTT) assay, and the anticancer effect of the NOAuNPs was evaluated by apoptosis and cell cycle analyses using flow cytometry.ResultsThe average size of the NPs was 56.4 nm. The intensities of the Au peaks from EDS analysis indicated that the AuNPs were synthesized successfully. Moreover, the in vitro antioxidant activities of the NO and NOAuNPs were evaluated; these materials gave values of 31.78 ± 1.71% and 31.62 ± 0.46%, respectively, in the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay at 200 g/mL and values of 25.89 ± 1.90% and 33.81 ± 0.62%, respectively, in the 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) assay. The NO and NOAuNPs gave values of 0.389 ± 0.027 and 0.308 ± 0.005, respectively, in the ferrous ion reducing antioxidant capacity (FRAP) assay and values of 0.078 ± 0.009 and 0.172 ± 0.027, respectively, in the copper ion reducing antioxidant capacity (CUPRAC) assay. When the DNA cleavage activities of NO and the NOAuNPs were evaluated via hydrolysis, both samples cleaved DNA starting at a concentration of 25 g/mL in the cell culture analysis, while the nanoformulation of the NO components gave greater therapeutic and anticancer effects. We determined that the Au nanoparticles were not toxic to A549 cells. Moreover, after treatment with the half-maximal inhibitory concentration (IC50), determined by the MTT assay with A549 cells, we found that at 24 and 48 h, while the necrosis rates were high in cells treated with NO, the rates of apoptosis were greater in cells treated with NOAuNPs. Notably, for anticancer treatment, activating apoptotic pathways that do not cause inflammation is preferred. We believe that these results will pave the way for the use of NOAuNPs in in vitro studies of other types of cancer.ConclusionIn this study, AuNPs were successfully synthesized from N. officinale extract. The biosynthesized AuNPs exhibited toxicity to and apoptotic effects on A549 lung cancer cells. Based on these findings, we suggest that green-synthesized AuNPs are promising new therapeutic agents for lung cancer treatment. However, since this was an in vitro study, further research should be performed in in vivo lung cancer models to support our findings and to explain the mechanism of action at the molecular level.

Calls to action on lung cancer management and research.

Lung cancer, the leading cause of cancer-related deaths globally, remains a pressing health issue despite significant medical advances. The New York Lung Cancer Foundation brought together experts from academia, the pharmaceutical and biotech industries as well as organizational leaders and patient advocates, to thoroughly examine the current state of lung cancer diagnosis, treatment, and research. The goal was to identify areas where our understanding is incomplete and to develop collaborative public health and scientific strategies to generate better patient outcomes, as highlighted in our "Calls to Action." The consortium prioritized 8 different calls to action. These include (1) develop strategies to cure more patients with early-stage lung cancer, (2) investigate carcinogenesis leading to lung cancers in patients without a history of smoking, (3) harness precision medicine for disease interception and prevention, (4) implement solutions to deliver prevention measures and effective therapies to individuals in under-resourced countries, (5) facilitate collaborations with industry to collect and share data and samples, (6) create and maintain open access to big data repositories, (7) develop new immunotherapeutic agents for lung cancer treatment and prevention, and (8) invest in research in both the academic and community settings. These calls to action provide guidance to representatives from academia, the pharmaceutical and biotech industries, organizational and regulatory leaders, and patient advocates to guide ongoing and planned initiatives.

Codelivery of CPT and siPHB1 with GSH/ROS Dual-Responsive Hybrid Nanoparticles Based on a [12]aneN3-Derived Lipid for Synergistic Lung Cancer Therapy.

The combination of small-interfering RNA (siRNA)-mediated gene silencing and chemotherapeutic agents for lung cancer treatment has attracted widespread attention in terms of a greater therapeutic effect, minimization of systemic toxicity, and inhibition of multiple drug resistance (MDR). In this work, three amphiphiles, CBN1-CBN3, were first designed and synthesized as a camptothecin (CPT) conjugate and gene condensation agents by the combination of CPT prodrugs and di(triazole-[12]aneN3) through the ROS-responsive phenylborate ester and different lengths of alkyl chains (with 6, 9, 12 carbon chains for CBN1-CBN3, respectively). CBN1-CBN3 were able to be self-assembled into liposomes with an average diameter in the range of 320-240 nm, showing the ability to effectively condense siRNA. Among them, CBN2, with a nine-carbon alkyl chain, displayed the best anticancer efficiency in A549 cells. In order to give nanomedicines a stealth property and PEGylation/dePEGylation transition, a GSH-responsive PEGylated TPE derivative containing a disulfide linkage (TSP) was further designed and prepared. A combination of CBN2/siRNA complexes and DOPE with TSP resulted in GSH/ROS dual-responsive lipid-polymer hybrid nanoparticles (CBN2-DP/siRNA NPs). In present GSH and H2O2, CBN2-DP/siRNA NPs were decomposed, resulting in the controlled release of CPT drug and siRNA. In vitro, CBN2-DP/siPHB1 NPs showed the best anticancer activity for suppression of about 75% of A549 cell proliferation in a serum medium. The stability of CBN2-DP/siRNA NPs was significantly prolonged in blood circulation, and they showed effective accumulation in the A549 tumor site through an enhanced permeability and retention (EPR) effect. In vivo, CBN2-DP/siPHB1 NPs demonstrated enhanced synergistic cancer therapy efficacy and tumor inhibition as high as 71.2%. This work provided a strategy for preparing lipid-polymer hybrid NPs with GSH/ROS dual-responsive properties and an intriguing method for lung cancer therapy.

Curcumin-Piperlongumine Hybrid Molecule Increases Cell Cycle Arrest and Apoptosis in Lung Cancer through JNK/c-Jun Signaling Pathway.

The instability of curcumin's structure and the toxic side effects of piperlongumine have limited their potential applications in cancer treatment. To overcome these challenges, we designed and synthesized a novel curcumin-piperlongumine hybrid molecule, 3-[(E)-4-hydroxy-3-methoxybenzylidene]-1-[(E)-3-(3,4,5-trimethoxyphenyl)acryloyl]piperidin-2-one (CP), using a molecular hybridization strategy. CP exhibited enhanced structural stability and safety compared with its parent compounds. Through in vitro and in vivo biological activity screenings, CP effectively inhibited cell proliferation, caused cell cycle arrest in the G2/M phase, and induced apoptosis. Mechanistically, CP-induced apoptosis was partially mediated by cell cycle arrest. Furthermore, we discovered that CP induces cell cycle arrest and apoptosis through the regulation of JNK signaling. These findings highlight the potential of CP as a promising therapeutic agent for lung cancer treatment.

Phytochemical composition of the diethyl ether extract of Artemisia lactiflora Wall. ex DC and its antimetastatic activity in human lung cancer cells

Artemisia lactiflora Wall. ex DC. is a traditional Chinese medicinal plant used in the treatment of menstrual and hepatic disorders due to its antioxidant and anti-inflammatory properties. However, its anti-metastatic activity, which is the clinical challenge of lung cancer treatment, has not yet been reported. From the diethyl ether extract of Artemisia lactiflora, the four terpenoids, including dihydroactinidiolide, megastigmatrienone, alpha-curcumene, and dehydrovomifoliol, were the most intense peaks observed using LC-MS/MS, whereas bis (2-ethylhexyl) phthalate was a contaminant. In a transwell assay, the A. lactiflora diethyl ether extract (32 μg/ml) and dihydroactinidiolide (250 μg/ml) markedly inhibited the migration and invasion of non-small cell lung cancer (NSCLC) cells, similar to the standard anti-metastatic drug (capmatinib). Western blot analysis revealed that mesenchymal N-cadherin is downregulated in NSCLC cells under the treatment conditions. The potential anti-metastatic property of dihydroactinidiolide is promising as a new candidate anti-metastatic agent for lung cancer treatment.

9,10-Dioxoanthracenyldithiocarbamates effectively inhibit the proliferation of non-small cell lung cancer by targeting multiple protein tyrosine kinases

Anthraquinones have attracted considerable interest in the realm of cancer treatment owing to their potent anticancer properties. This study evaluates the potential of a series of new anthraquinone derivatives as anticancer agents for non-small-cell lung cancer (NSCLC). The compounds were subjected to a range of tests to assess their cytotoxic and apoptotic properties, ability to inhibit colony formation, pro-DNA damage functions, and capacity to inhibit the activity of tyrosine kinase proteins (PTKs). Based on the research findings, it has been discovered that most active derivatives (i84, i87, and i90) possess a substantial capability to impede the viability of NSCLC while having mostly a negligible effect on the human kidney cell line. Moreover, the anthraquinones displayed pro-apoptotic and genotoxic attributes while blocking the phosphorylation of multiple PTKs. Collectively, our findings indicate that these derivatives may demonstrate promising potential as effective anticancer agents for lung cancer treatment.

Molecular regulation of autophagy and suppression of protein kinases by aescin, a triterpenoid saponin impedes lung cancer progression

Lung cancer is the most common and lethal cancer worldwide, yet there are no adequate and novel medications to control this illness. Previous reports suggested the potential of protein kinases to target lung cancer by regulating autophagy. This study establishes the role of aescin, a triterpenoid saponin, in targeting protein kinases responsible for lung cancer proliferation and mobility. The experimental data revealed that aescin significantly impedes lung cancer cell proliferation by downregulating protein kinases such as AKT, mTOR, MEK, and ERK. Downregulation of AKT-mTOR may promote a string of events inducing cytotoxic autophagy-mediated apoptosis in the presence of aescin. Besides, aescin decreases mobility and invasion by downregulating HIF-1α and VEGF gene expressions. Moreover, it successfully monitors EGFR gene expression, improves lung histology, and regulates biochemical parameters in a pre-clinical DEN-induced lung cancer model. Aescin was observed to be safe and non-toxic in both in silico toxicity predictions and ex vivo erythrocyte fragility assays. Hence, this study elucidates the molecular mechanism of aescin in targeting protein kinases and suggests that it could be a safer and more viable therapeutic agent for lung cancer treatment.

Mychonastes sp. 247 Induces Apoptosis of A549 Human Lung Cancer Cells by Promoting STRA6-Mediated Reactive Oxygen Species Production

Mychonastes sp. 247 is a newly isolated freshwater microalga. Mychonastes sp. 247 methanolic extract (ME) suppresses the growth of A549 human non-small-cell lung cancer (NSCLC) cells. However, the underlying mechanism of this anticancer effect remains unclear. The present study aimed to reveal the underlying mechanism of the anticancer effect of ME in A549 cells. The components of ME, their cytotoxicity in normal cells, and their inhibitory effect on the growth and migration of two-dimensional and three-dimensional cultured cancer cells were investigated. We also showed that ME upregulated the mRNA levels of signaling receptors and transporters of retinol (STRA6) and cytochrome P450 family 26 subfamily B member 1, and increased the protein expression of phosphorylated c-Jun N-terminal kinase, B-cell lymphoma protein 2/(Bcl-2)-associated X (Bcl-2/Bax), and cleaved caspase-3. Moreover, co-treatment with N-acetyl-L-cysteine reversed the ME-induced changes in the levels of STRA6 and reactive oxygen species (ROS), confirming their role in the ME-mediated anticancer effect. To the best of our knowledge, this is the first study elucidating the pathway by which ME induces anticancer effects in lung cancer cells. Our results reveal that ME induces NSCLC apoptosis by regulating ROS levels via the STRA6 pathway, suggesting ME as a prospective anticancer agent for lung cancer treatment.

Nanostructured Lipid Carrier Co-Loaded with Docetaxel and Magnetic Nanoparticles: Physicochemical Characterization and In Vitro Evaluation.

Lung cancer is currently the most prevalent cause of cancer mortality due to late diagnosis and lack of curative therapies. Docetaxel (Dtx) is clinically proven as effective, but poor aqueous solubility and non-selective cytotoxicity limit its therapeutic efficacy. In this work, a nanostructured lipid carrier (NLC) loaded with iron oxide nanoparticles (IONP) and Dtx (Dtx-MNLC) was developed as a potential theranostic agent for lung cancer treatment. The amount of IONP and Dtx loaded into the Dtx-MNLC was quantified using Inductively Coupled Plasma Optical Emission Spectroscopy and high-performance liquid chromatography. Dtx-MNLC was then subjected to an assessment of physicochemical characteristics, in vitro drug release, and cytotoxicity. Dtx loading percentage was determined at 3.98% w/w, and 0.36 mg/mL IONP was loaded into the Dtx-MNLC. The formulation showed a biphasic drug release in a simulated cancer cell microenvironment, where 40% of Dtx was released for the first 6 h, and 80% cumulative release was achieved after 48 h. Dtx-MNLC exhibited higher cytotoxicity to A549 cells than MRC5 in a dose-dependent manner. Furthermore, the toxicity of Dtx-MNLC to MRC5 was lower than the commercial formulation. In conclusion, Dtx-MNLC shows the efficacy to inhibit lung cancer cell growth, yet it reduced toxicity on healthy lung cells and is potentially capable as a theranostic agent for lung cancer treatment.

Anacyclus pyrethrum extract significantly destroyed lung cancer cell line (A549) by inducing apoptosis

BackgroundLung cancer is one of the serious human health problems and many researchers have focused on identifying new therapeutic agents and effective therapies. Recently, herbal medicines have been used for the treatment of various diseases such as cancer. This research aimed to investigate the potential anti-tumoral activity and clarify the respective mechanisms of Anacyclus pyrethrum plant extract on the A549 lung cancer cell line. MethodsTo determine the cytotoxic effects of the Anacyclus pyrethrum extract on lung cancer cells, Trypan blue exclusion and MTT assay were performed. To show the induction of apoptosis by Anacyclus pyrethrum extract, flow cytometry assay was conducted. Quantitative real time PCR test was used to quantify the expressions of Bcl-2, Caspase-3, − 8, and − 9 genes, which are involved in apoptosis regulation. Also, cell cycle analysis was conducted by using flow cytometry. ResultsThe Anacyclus pyrethrum plant extract could significantly inhibit lung cancer cell (A549) proliferation. Flow cytometry assay demonstrated that Anacyclus pyrethrum induced apoptosis. The messenger RNA (mRNA) expression levels of Caspase-3 and Caspase-9 were significantly upregulated by Anacyclus pyrethrum treatment, while the Bcl-2 gene was downregulated. The flow cytometry confirmed that cell cycle arrest occurred at the G1 phase. ConclusionOur experiment showed that Anacyclus pyrethrum plant extract could considerably inhibit lung cancer cell growth by inducing of the intrinsic apoptosis pathway. Therefore, it may be a useful agent for lung cancer treatment.

7,8-Diacetoxy-3-(4-methylsulfonylphenyl)-4-phenylcoumarin Induces ROS-dependent Cell Death in the A549 Human Lung Cancer Cell Line.

Coumarins comprise of a very large class of naturally occurring compounds with growing interest in their synthesis and possible applications in the treatment of various diseases. We herein report the in-vitro cytotoxic activity of 3,4-Diarylcoumarins (4a-i) in A549 (lung) and PC-3 (prostate) cancer cell lines. The cytotoxic activity was evaluated using crystal violet dye-binding. The most active compound effect on the cell-cycle phases, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) production and apoptosis were also evaluated. Among the synthesized compounds that were evaluated, 7,8-Diacetoxy-3-(4-(methylsulfonyl)phenyl)-4-phenylcoumrin (4f) showed highest cytotoxicity (CC50=13.5%±0.15μM) in A549 cancer cell line. The mechanism of its cytotoxic action indicated significant cell arrest in G1/G0, S and G2 phases of the cell cycle, loss of mitochondrial membrane potential (MMP), increase in reactive oxygen species (ROS) production and induction of apoptotic cell death. The cell viability result of pretreated A549 cells with antioxidant N-acetylcysteine (NAC), followed by compound 4f treatment confirmed ROS-dependent cell death. The presence of 3-4-methylsulfonyl and 7,8-diacetoxy groups on 3,4-Diarylcoumarin is critical in modulating higher cytotoxic activity and could serve as a valuable template for the development of novel synthetic compounds as potential anticancer agents for lung cancer treatment.

HDAC Inhibitory and Anti-Cancer Activities of Curcumin and Curcumin Derivative CU17 against Human Lung Cancer A549 Cells.

Previous research reported that the curcumin derivative (CU17) inhibited several cancer cell growths in vitro. However, its anticancer potential against human lung cancer cells (A549 cell lines) has not yet been evaluated. The purpose of this research was to examine the HDAC inhibitory and anti-cancer activities of CU17 compared to curcumin (CU) in A549 cells. An in vitro study showed that CU17 had greater HDAC inhibitory activity than CU. CU17 inhibited HDAC activity in a dose dependent manner with the half-maximal inhibitory concentration (IC50) value of 0.30 ± 0.086 µg/mL against HDAC enzymes from HeLa nuclear extract. In addition, CU17 could bind at the active pockets of both human class I HDACs (HDAC1, 2, 3, and 8) and class II HDACs (HDAC4, 6, and 7) demonstrated by molecular docking studies, and caused hyperacetylation of histone H3 (Ac-H3) in A549 cells shown by Western blot analysis. MTT assay indicated that both CU and CU17 suppressed A549 cell growth in a dose- and time-dependent manner. Besides, CU and CU17 induced G2/M phase cell cycle arrest and p53-independent apoptosis in A549 cells. Both CU and CU17 down-regulated the expression of p53, p21, Bcl-2, and pERK1/2, but up-regulated Bax expression in this cell line. Although CU17 inhibited the growth of lung cancer cells less effectively than CU, it showed less toxicity than CU for non-cancer cells. Accordingly, CU17 is a promising agent for lung cancer treatment. Additionally, CU17 synergized the antiproliferative activity of Gem in A549 cells, indicating the possibility of employing CU17 as an adjuvant treatment to enhance the chemotherapeutic effect of Gem in lung cancer.

Paeonol inhibits human lung cancer cell viability and metastasis in vitro via miR-126-5p/ZEB2 axis.

Paeonol exerted an effect in lung cancer, but the underlying mechanism remained vague. In this research, we assessed the effects of Paeonol and microRNA (miR)-126-5p on the viability, migration, invasion, and epithelial-mesenchymal transition (EMT) of lung cancer cells. Lung cancer cells and BEAS-2B cells were treated with Paeonol, and viability was detected by 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di- phenytetrazoliumromide (MTT) assay. The migration and invasion of lung cancer cells after treatment with Paeonol at 40 μg/mL or 80 μg/mL were detected by wound healing assay and Transwell assay, respectively. The effects of Paeonol on transforming growth factor-β1 (TGF-β1)-induced EMT and relative expressions of EMT-related proteins were determined using Western blot. The target gene of miR-126-5p and the binding sites between them were predicted by TargetScan, and confirmed using dual-luciferase reporter assay. Relative expressions of miR-126-5p, its target gene and EMT-related proteins were determined by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Rescue assay was performed to analyze the relation between Paeonol and miR-126-5p. Paeonol down-regulated cell viability and inhibited migration, invasion and TGF-β1-induced EMT while up-regulating miR-126-5p expression in lung cancer cells as the dose increased. However, miR-126-5p inhibitor could reverse the effect of Paeonol. ZEB2 was the target gene of miR-126-5p, and silencing ZEB2 expression reversed the effects of miR-126-5p downregulation. Paeonol also regulated the expression of ZEB2 in lung cancer cells, and this regulation depends on the regulation of miR-126-5p. Paeonol inhibits human lung cancer cell viability and metastasis via the miR-126-5p/ZEB2 axis, and could be adopted as a potential agent for lung cancer treatment.

Norcycloartocarpin targets Akt and suppresses Akt-dependent survival and epithelial-mesenchymal transition in lung cancer cells.

In searching for novel targeted therapeutic agents for lung cancer treatment, norcycloartocarpin from Artocarpus gomezianus was reported in this study to promisingly interacted with Akt and exerted the apoptosis induction and epithelial-to-mesenchymal transition suppression. Selective cytotoxic profile of norcycloartocarpin was evidenced with approximately 2-fold higher IC50 in normal dermal papilla cells (DPCs) compared with human lung cancer A549, H460, H23, and H292 cells. We found that norcycloartocarpin suppressed anchorage-independent growth, cell migration, invasion, filopodia formation, and decreased EMT in a dose-dependent manner at 24 h, which were correlated with reduced protein levels of N-cadherin, Vimentin, Slug, p-FAK, p-Akt, as well as Cdc42. In addition, norcycloartocarpin activated apoptosis caspase cascade associating with restoration of p53, down-regulated Bcl-2 and augmented Bax in A549 and H460 cells. Interestingly, norcycloartocarpin showed potential inhibitory role on protein kinase B (Akt) the up-stream dominant molecule controlling EMT and apoptosis. Computational molecular docking analysis further confirmed that norcycloartocarpin has the best binding affinity of -12.52 kcal/mol with Akt protein at its critical active site. As Akt has recently recognized as an attractive molecular target for therapeutic approaches, these findings support its use as a plant-derived anticancer agent in cancer therapy.

A novel mechanism of lung cancer inhibition by methionine enkephalin through remodeling the immune status of the tumor microenvironment

This study examined the antitumor effect of methionine enkephalin (MENK) against lung cancer in vivo and in vitro and explored the underlying mechanisms. Changes in the immune status of the tumor microenvironment (TME) in response to MENK administration were examined in mice. MENK significantly inhibited the proliferation of lung cancer cells in vivo and in vitro by regulating the Wnt/β-catenin pathway and causing cell cycle arrest at the G0/G1 phase. Knockdown of opioid growth factor receptor abolished the effect of MENK on lung cancer cells. The immune status of the TME of mice differed between the MENK and control groups. MENK increased the infiltration of M1-type macrophages, natural killer cells, CD8+ T cells, CD4+ T cells, and dendritic cells into the TME, and decreased the proportion of myeloid inhibitory cells and M2-type macrophages. Immunohistochemical analysis of the expression of cytokines in the TME showed that MENK upregulated IL-15, IL-21, IFN-γ, and granzyme B and downregulated IL-10 and TGF-β1 in mice. Taken together, these finding indicate that MENK may be a potential agent for lung cancer treatment in the future, especially for overcoming immune escape and immune resistance.

The novel FAT4 activator jujuboside A suppresses NSCLC tumorigenesis by activating HIPPO signaling and inhibiting YAP nuclear translocation

FAT atypical cadherin 4 (FAT4) has been identified as a tumor suppressor in lung cancers. However, no agent for lung cancer treatment targeting FAT4 has been used in the clinic. Jujuboside A (JUA) is a major active compound in Semen Ziziphi Spinosae. Semen Ziziphi Spinosae is a traditional Chinese herbal medicine used clinically for tumor treatment to improve patients’ quality of life. However, the anti-lung cancer activity and the underlying mechanisms of JUA are not yet fully understood. Here, we demonstrated the anti-lung cancer activity of JUA in two lung cancer mice models and three non-small cell lung cancer (NSCLC) cell lines, and further illustrated its underlying mechanisms. JUA suppressed the occurrence and development of lung cancer and extended mice survival in vivo, and suppressed NSCLC cell activities through cell cycle arrest, proliferation suppression, stemness inhibition and senescence promotion. Moreover, JUA directly bound with and activated FAT4, subsequently activating FAT4-HIPPO signaling and inhibiting YAP nuclear translocation. Knockdown of FAT4 diminished JUA’s effects on HIPPO signaling, YAP nuclear translocation, cell proliferation and cellular senescence. In conclusion, JUA significantly suppressed NSCLC tumorigenesis by regulating FAT4-HIPPO-YAP signaling. Our findings suggest that JUA is a novel FAT4 activator that can be developed as a promising NSCLC therapeutic agent targeting the FAT4-HIPPO-YAP pathway.

Engineering of gemcitabine coated nano-graphene oxide sheets for efficient near-infrared radiation mediated in vivo lung cancer photothermal therapy

Gemcitabine (GEM) and its derivatives of deoxycytosine is a promising anticancer candidate which is effective for the treatment of various cancers including lung cancer via cascade targetting Erk/Mek/Raf/Ras pathway and blocking the proliferation of the tumor cells. In this present work, we have described reduced graphene oxide (rGO) in the presence of anticancer utilizing ascorbic acid as reducing agents for lung cancer treatment. GEM reduced graphene oxide (termed as GEM-rGO) has resulted in a smooth and transparent morphological surface, which was confirmed by various spectroscopical investigations. The anticancer drug-loaded rGO has displayed remarkable cytotoxic activities against a panel of lung cancer cell lines when compared to the untreated lung cancer cells. Further, we examined the morphological observation of the cancer cell death was monitored through the fluorescence microscopic examinations. In addition, the cell deaths of the lung cancer cells were observed by the flow cytometry analyses. In addition, the non-toxic nature of potent GEM-rGO and GEM-rGO + NIR was confirmed by in vivo systemic toxicity analysis. Besides, the higher safety feature of the GEM-rGO and GEM-rGO + NIR was evidenced by histological analyses of the mice organs. The subcutaneous injection of GEM-rGO and GEM-rGO + NIR into mice bearing A549 xenografts more effectively inhibited the tumor than the free GEM. Based on the outcomes, we can summarise that the GEM reduced graphene oxide (GEM-rGO) can be used as a promising drug candidate for the treatment of lung cancer in the future.

Therapeutic potential of IBP as an autophagy inducer for treating lung cancer via blocking PAK1/Akt/mTOR signaling

Lung cancer is the most frequent and fatal malignancy in humans worldwide, yet novel successful drugs for control of this disease are still lacking. Ipomoea batatas polysaccharides (IBPs) have been implicated in inhibiting diverse cancer types, but their functions in mitigating lung cancer are largely unknown. In this study, we identify a role of IBP in inhibiting lung cancer proliferation. We found that IBP significantly impedes the proliferation of lung cancer cells by inducing cytostatic macroautophagy both in vitro and in vivo. Mechanistically, IBP specifically promotes ubiquitination-mediated degradation of PAK1 (p21-activated kinase 1) and blocks its downstream Akt1/mTOR signaling pathway, leading to increased autophagic flux. In lung cancer xenografts in mice, IBP-induced cytostatic autophagy suppresses tumor development. Through site-directed mutational analysis, the underlying signaling augments ubiquitination via PAK1-ubiquitin interaction. Collectively, this work unravels the molecular mechanism underpinning IBP-induced cytostatic autophagy in lung cancer and characterizes IBP as a potential therapeutic agent for lung cancer treatment.

Methylation of RILP in lung cancer promotes tumor cell proliferation and invasion.

Rab-interacting lysosomal protein (RILP) has been suggested to perform as a tumor suppressor in breast and prostate cancer cell lines. However, its expression profile and functional role in lung cancer have never been investigated. We applied the well-established cancer genomic database-The Cancer Genome Atlas to compare the RILP expression and methylation between lung cancer tissues and normal tissues. The potential correlation of RILP with clinical characteristics of lung cancer patients (e.g., stages, smoking, TP53, and methylation) was also be explored. Our results showed that the downregulation of RILP and upregulation of RILP methylation were identified in lung cancer tissues compared to normal healthy tissues. Downregulation of RILP was positively associated with lung cancer later stage (N3), smoking history, TP53 mutation, and poor prognosis, as well as inversely correlated with DNA (cytosine-5)-methyltransferase 1 (DNMT1) expression. Demethylation treatment enhanced RILP expression in lung cancer cells, suggesting hypermethylation is responsible for RILP silencing in lung cancer. We further found that RILP depletion promoted lung cancer cell proliferation, migration, and invasion.We concluded that RILP acts as a tumor suppressor in lung cancer cells. Our results provided the theoretical basis for developing RILP-targeting or demethylating agents for lung cancer treatment.

Ru(II) Complexes Bearing O, O-Chelated Ligands Induced Apoptosis in A549 Cells through the Mitochondrial Apoptotic Pathway.

Two new Ru(II) complexes containing O, O-chelated ligands, Ru(dip)2(SA) (Ru-1) and Ru(dmp)2(SA) (Ru-2) (dip = 4,7-diphenyl-1,10-phenanthroline; dmp = 2,9-dimethyl-1,10-phenanthroline; SA = salicylate) were synthesized to evaluate their cytotoxicity in vitro. These complexes were found to exhibit moderate antitumor activity to different types of human cancers, including A549 (human lung carcinoma), MCF-7 (breast cancer), HeLa (human cervical cancer), and HepG2 (human hepatocellular carcinoma) cell lines, but displayed low toxicity to human normal cell lines BEAS-2B (immortalized human bronchial epithelial cells) when compared with that of cisplatin. Further studies revealed that these complexes could induce apoptosis in A549 cells, including activating caspase family proteins and poly (ADP-ribose) polymerase (PARP), reducing Bcl-2/Bax and Bcl-xl/Bad ratio, enhancing cellular reactive oxygen species (ROS) accumulation, triggering DNA damage, decreasing mitochondrial membrane potential (MMP), and leading cytochrome c release from mitochondria. Notably, complex Ru-1 showed low toxicity to developing zebrafish embryos. The obtained results suggest that these new synthetic complexes have the potential to be developed as low-toxicity agents for lung cancer treatment.