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The therapeutic application and dose of cisplatin are limited due to its toxicity to normal cells. Therefore, combination treatments might be the solution with a low dose of cisplatin. The combination effect of nanosecond pulsed high-power microwave (HPM) with cisplatin has not been investigated before. In this work, we aimed to investigate and assess the potential synergistic effects and most likely underlying mechanisms resulting from the combination of nanosecond pulsed HPM and cisplatin. Three cancer (SKOV3, H460, and MDA-MB231) and two normal (MRC5 and HGF) cell lines underwent separate treatments with HPM and cisplatin, as well as a combined treatment. A higher reduction of viability was observed in cancer cells using combination treatments following 24-h incubation. Cell death, membrane permeability, and intracellular reactive oxygen species (ROS) levels exhibit a noteworthy increase in response to combined 60 pulses of HPM (HPM60) and cisplatin (0.5 μM) treatments compared to control and individual treatments. Elevated γ-H2AX levels indicate DNA double-strand breaks in combined treatments. Additionally, upregulation of ATR/ATM, Chk1/Chk2, P53, and caspase 3/8, Bax, PARP, and Bcl2 confirms DNA damage and mitochondrial dysfunction, leading to apoptosis. Remarkably, half maximal inhibitory concentration (IC 50) results showed that HPM60 and cisplatin (0.5 μM) resulted in 16 times higher cell death in SKOV3 and H460 cells compared to cisplatin alone. Moreover, the efficacy of this combined treatment led to an over 50 % decrease in the viability of cancer cells. On the other hand, normal cells (MRC5 and HGF) exhibited only a minor 3–5 % decrease in viability under the same treatment conditions. The obtained results elucidate the cellular mechanisms driving cell apoptosis/death, offering insights for potential advancements in cancer therapy through the combined application of nanosecond pulses of HPM and cisplatin. This serves as a first step for future investigations in this domain. [Display omitted] • Nanosecond pulsed high power microwaves (HPM) generated at frequency 3.5 GHz, delivering 2 mJ/pulse electromagnetic energy to cells • Cell death, membrane permeability, and intracellular ROS levels increased in response to combined HPM60 and cisplatin, compared to control and individual treatments • Elevated γ-H2AX levels indicate DNA double-strand breaks in combined (HPM60+cisplatin) treatments • Upregulation of ATR/ATM, Chk1/Chk2, P53 and caspase 3/8, Bax, PARP, Bcl2 confirms DNA damage and mitochondrial dysfunction, leading to apoptosis • HPM60 and cisplatin (0.5 μM) resulted 16-fold increase of cell death in SKOV3 and H460 cells • The efficacy of this combined treatment led to over 50 % decrease in viability of cancer cells [ABSTRACT FROM AUTHOR]

Despite its potential against several carcinomas, the pharmacological efficacy of silibinin (SLB) is hampered by poor solubility, absorption, and oral bioavailability. To face these issues, we developed polylactic-co-glycolic acid (PLGA) nanoparticles (NPs) coated with hydrophilic polyethene oxide (PEO) for controlled and targeted SLB delivery. NPs were produced at two different SLB loadings and presented a spherical shape with smooth surfaces and stable size in water and cell culture medium. The encapsulation efficiencies were found to be >84%, and thermal analysis revealed that the SLB was present in an amorphous state within the NPs. In vitro SLB release experiments revealed that at the lowest SLB loading, desorption of the active molecule from the surface or nanoporosities of the NPs mainly dictates release. In contrast, at the highest SLB loading, diffusion primarily regulates release, with negligible contributions from other mechanisms. Cell experiments showed that, compared with the free drug, SLB loaded in the produced NPs significantly increased the bioactivity against H1299, H1975, and H358 cells. [ABSTRACT FROM AUTHOR]

Ornithogalum is a genus of wild herb species widely used as food and in traditional medicine. This study investigated some of the biologically active properties of Ornithogalum balansae grown in the eastern Black Sea region of Türkiye. The investigations were carried out using the methanolic extracts of the plant's aerial and bulbs (B1 and B2) parts. The phenolic composition was examined as total phenolic content (TPC), total flavonoid content (TFC), and HPLC-PDA. The antioxidant capacity of the extracts was tested based on ferric reducing/antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging methods. The anti-proliferative activity was tested against metastatic cell lines H1299 and H209, non-small-cell lung A549, and fibroblast MRC-5 cell lines using MTT and trypan blue methods. Wound-healing and invasion chamber assays were used to determine the inhibitory effects of the extracts on migration and invasion, respectively. The extract of the aerial part contained a large number of phenolic substances and high antioxidant capacity. The extract exhibited a significant anti-proliferative effect on the human lung cancer cells (A549 and H209), with IC50 values of 0.97 ± 0.04 and 1.06 ± 0.07 µg/mL, respectively. Moreover, the aerial part exhibited inhibition of migratory and invasive capacities in A549 cells at a concentration of 1.50 µg/mL. The findings associated with O. balansae suggest a promising therapeutic potential against lung cancer cells. [ABSTRACT FROM AUTHOR]

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the "dose and LET" physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LETd) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LETd. However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LETd (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LETd alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model. [ABSTRACT FROM AUTHOR]

Abstract The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the “dose and LET” physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LET d ) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LET d . However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LET d (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LET d alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model.

Background and purpose: It is still a great challenge to clarify the signal molecules that mediate the communication between cancer-associated fibroblasts (CAFs) and tumor cells. These signal molecules are very important for cancer metastasis. The purpose of this study was to explore the communication mechanism of pleckstrin-2/miR-196a signal axis mediated by lung cancer cells in tumor microenvironment. Methods: Human lung adenocarcinoma cell line H1299 and human embryonic lung cell MRC-5 were selected as the research objects. H1299 cells were transfected with lentivirus (PLEK2) expressing PLEK2 and Vector control, and exosomes (Vector_exo, PLEK2_exo) were isolated after 24 h of transfection. MRC-5 cells were transfected with miR-196a mimetic or inhibitor. The expressions of PLEK2 and epithelial-mesenchymal transition (EMT)-related proteins were analyzed by Western blot. The expression of miR-196a was analyzed by polymerase chain reaction (PCR), and the metastasis and invasion ability of cells were determined by transwell assay. Six female BALB/c-nu mice were randomly divided into Vector group and PLEK2 group, with 3 mice in each group. Mice in each group were injected with H1299 cells transfected with Vector or PLEK2 through the tail vein. After 4 weeks, lung tissue was taken out for H-E staining and immunohistochemical staining to analyze the expression of α-smooth muscle actin (α-SMA). All animal experiments were approved by the ethics committee of First Hospital of Changsha City (Changsha Hospital, Xiangya School of Medicine, Central South University) (ethics number: EI-2021-103). Results: Compared with the Vector group, the number of pulmonary metastatic nodules and the expression of α-SMA in metastatic cancer in PLEK2 group increased significantly (P

Background and purpose: It is still a great challenge to clarify the signal molecules that mediate the communication between cancer-associated fibroblasts (CAFs) and tumor cells. These signal molecules are very important for cancer metastasis. The purpose of this study was to explore the communication mechanism of pleckstrin-2/miR-196a signal axis mediated by lung cancer cells in tumor microenvironment. Methods: Human lung adenocarcinoma cell line H1299 and human embryonic lung cell MRC-5 were selected as the research objects. H1299 cells were transfected with lentivirus (PLEK2) expressing PLEK2 and Vector control, and exosomes (Vector_exo, PLEK2_exo) were isolated after 24 h of transfection. MRC-5 cells were transfected with miR-196a mimetic or inhibitor. The expressions of PLEK2 and epithelial-mesenchymal transition (EMT)-related proteins were analyzed by Western blot. The expression of miR-196a was analyzed by polymerase chain reaction (PCR), and the metastasis and invasion ability of cells were determined by transwell assay. Six female BALB/c-nu mice were randomly divided into Vector group and PLEK2 group, with 3 mice in each group. Mice in each group were injected with H1299 cells transfected with Vector or PLEK2 through the tail vein. After 4 weeks, lung tissue was taken out for H-E staining and immunohistochemical staining to analyze the expression of α-smooth muscle actin (α-SMA). All animal experiments were approved by the ethics committee of First Hospital of Changsha City (Changsha Hospital, Xiangya School of Medicine, Central South University) (ethics number: EI-2021-103). Results: Compared with the Vector group, the number of pulmonary metastatic nodules and the expression of α-SMA in metastatic cancer in PLEK2 group increased significantly (P＜0.001). Compared with Vector group, the expression level of miR-196a in H1229 cells in PLEK2 group increased significantly (P＜0.05), and the expression level of miR-196a was significantly higher in PLEK2_exo than in Vector_exo (P＜0.05). Compared with Vector_exo group, the expression levels of miR-196a, α-SMA and fibroblast activation protein (FAP) in MRC-5 cells in PLEK2_exo group increased significantly (P＜0.05). Compared with the negative control (NC), the expression levels of α-SMA and FAP in MRC-5 cells transfected with miR-196a increased significantly (P＜0.05). On the contrary, by transfection with miR-196a inhibitors (si-miR-196a#1 and si-miR-196a#), the expression levels of α-SMA and FAP were significantly inhibited (P＜0.05). Compared with NC-CM group, the number of metastatic cells, invasive cells and the expression of vimentin in miR- 196a-CM group increased significantly (P＜0.001), and the expression of E-cadherin decreased significantly (P＜0.001). In addition, compared with Vector_exo-CM group, PLEK2_exo-CM group had significant increase in number of metastatic and invasive cells and the expression of vimentin (P＜0.01), and significant decrease in the expression of E-cadherin (P＜0.001). Conclusion: Upregulation of PLEK2 can enhance the level of exosomes miR-196a derived from lung cancer cells, thereby promoting the activation of CAFs. The activated CAFs can further enhance the invasive ability of lung cancer cells. [ABSTRACT FROM AUTHOR]

Currently, chemotherapy is one of the most practiced approaches for the treatment of cancers. However, existing chemotherapeutic drugs have poor aqueous solubility, poor selectivity, higher systematic toxicity, and poor target accumulation. In this study, we designed and synthesized a boronic acid/ester-based pH-responsive nano-valve that specifically targets the microenvironment in cancer cells. The nano-valve comprises phenylboronic acid-coated mesoporous silica nanoparticles (B-MSN) loaded with polyphenolic compound Rosmarinic acid (ROS-B-MSN). The nano-valve was further coated with lignin (LIG) to achieve our desired LIG-ROS-BMSN nano-valve for targeted chemotherapy against Hep-G2 and NCI-H460 cell lines. The structure and properties of NPs were characterized by Fourier-transformed infrared spectroscopy (FTIR), Scanning Electron Microscopy (SEM) in combination with EDX, and Dynamic light scattering (DLS). The outcomes revealed that the designed LIG-ROS-BMSN were in the nanorange (144.1 ± 0.70 nm), had negative Zeta potential (-15.7 ± 0.46 mV) and had a nearly spherical morphology. In vitro, drug release investigations showed a controlled pH-dependent release profile under mild acidic conditions that could enhance the targeted chemotherapeutic response against cancer in mild acidic environments. The obtained LIG-ROS-BMSN nano valve achieved significantly lower IC50 values of (1.70 ± 0.01 μg/mL and 3.25 ± 0.14 μg/mL) against Hep-G2 and NCI-H460 cell lines as compared to ROS alone, which was (14.0 ± 0.7 μg/mL and 29.10 ± 0.25 μg/mL), respectively. The cellular morphology before and after treatment was further confirmed via inverted microscopy. The outcomes of the current study imply that our designed LIG-ROS-BMSN nanovalve is a potential carrier for cancer chemotherapeutics. [ABSTRACT FROM AUTHOR]

Extensive research on medicinal herbs for bioactive compounds proposes that they could replace synthetic drugs, reducing side effects and economic burdens. Especially, interest in the synergistic benefits of natural products is increasing, implying that their combined use may enhance therapeutic effectiveness. This study aimed to explore the synergetic effects of turmeric (Curcuma longa L.) and black pepper (Piper nigrum L.) extract on lung normal (MRC-5) and cancer (A549 and NCI-H292) cell lines. The turmeric extract (TM) only affected the lung cancer cell lines, but it had no impact on the MRC-5 cell line. On the other hand, the black pepper extract (BP) did not cause any damage to either the lung normal or cancer cell lines, even at concentrations of up to 400 µg/mL. Response surface methodology was used to predict the ideal synergistic concentrations (EC50) of TM and BP, which were found to be 48.5 and 241.7 µg/mL, respectively. Notably, the selected condition resulted in higher cytotoxicity compared to the exposure to TM alone, indicating a potent synergetic effect. The rate of curcumin degradation under this combined treatment was significantly decreased to 49.72 ± 5.00 nmol/h/µg for A549 cells and 47.53 ± 4.78 nmol/h/µg for NCI-H292 cells, respectively, as compared to curcumin alone. Taken together, this study confirmed the potent synergistic effect of TM and BP on lung cancer cell lines. Further research is required to identify their specific synergetic mechanisms. Our findings provide crucial foundational data on the synergistic effects of TM and BP.

This article deals with the antibacterial and anticancer potential of secondary metabolites produced by actinomycetes also reported as actinobacteria, Microbacterium proteolyticum (MN560041), and Streptomycetes rochei, where preliminary studies were done with the well diffusion method. These actinobacteria's silver nanoparticles were synthesized and characterized using transmission electron microscopy (TEM) and UV‐Visible spectroscopy. Anticancer was measured using the MTT test, reactive oxygen species (ROS) generation measured with DCFDA, mitochondrial membrane potential (MMP) measurement, and DAPI fluorescence intensity activity was measured in treated and non‐treated cancerous cells. The IC50 value for 5‐FU (a), LA2(O) (b), LA2(R) (c), LA2(ON) (d), and LA2(RN) (e) was obtained at 3.91 μg/mL (52.73% cell viability), 56.12 μg/mL (52.35% cell viability), 44.90 μg/mL (52.3% cell viability), 3.45 μg/mL (50.25% cell viability), and 8.05 μg/mL (48.72% cell viability), respectively. TEM micrographs revealed discrete, well‐separated AgNPs particles of size 7.88 ± 2 to 12.86 ± 0.24 nm. Gas chromatography‐mass spectrometry was also performed to detect the compounds in bioactive metabolites where n‐hexadecanoic acid was obtained as the most significant one. MTT test showed a substantial decline in A549 cell viability (up to 48.72%), 2.75‐fold increase in ROS generation was noticed in comparison to untreated A549 lung cancer cells when measured with DCFDA. A total of 0.31‐fold decrease in MMP and 1.74‐fold increase in DAPI fluorescence intensity compared to untreated A549 lung cancer cells suggests that the synthesized nanoparticles promote apoptosis in cancerous cells. Our findings suggests that the secondary metabolites of M. proteolyticum and S. rochei in nanoparticle form can be used as a significant compound against lung cancers. Significance statement: The current study has shown that these novel and rare actinobacteria Microbacterium proteolyticum and Streptomycetes rochei can produce a wide range of bioactive compounds which could serve as potential sources for future anticancer drug development. [ABSTRACT FROM AUTHOR]

Ornithogalum is a genus of wild herb species widely used as food and in traditional medicine. This study investigated some of the biologically active properties of Ornithogalum balansae grown in the eastern Black Sea region of Türkiye. The investigations were carried out using the methanolic extracts of the plant’s aerial and bulbs (B1 and B2) parts. The phenolic composition was examined as total phenolic content (TPC), total flavonoid content (TFC), and HPLC-PDA. The antioxidant capacity of the extracts was tested based on ferric reducing/antioxidant power (FRAP) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging methods. The anti-proliferative activity was tested against metastatic cell lines H1299 and H209, non-small-cell lung A549, and fibroblast MRC-5 cell lines using MTT and trypan blue methods. Wound-healing and invasion chamber assays were used to determine the inhibitory effects of the extracts on migration and invasion, respectively. The extract of the aerial part contained a large number of phenolic substances and high antioxidant capacity. The extract exhibited a significant anti-proliferative effect on the human lung cancer cells (A549 and H209), with IC50 values of 0.97 ± 0.04 and 1.06 ± 0.07 µg/mL, respectively. Moreover, the aerial part exhibited inhibition of migratory and invasive capacities in A549 cells at a concentration of 1.50 µg/mL. The findings associated with O. balansae suggest a promising therapeutic potential against lung cancer cells.

Polo-like protein kinase 1 (PLK1) plays a key role in lung cancer cell mitosis. The knockout of PLK1 gene by the CRISPR–Cas9 system can effectively inhibit the proliferation of tumor cells, but there is no suitable vector for in vivo delivery. In this study, CRISPR–Cas9 gene knockout plasmids encoding sgRNA, Cas9 and green fluorescent protein were constructed. Then, the plasmids were packaged with liposome (Lip) and cholesterol-modified Antheraea pernyi silk fibroin (CASF) to obtain the CASF/Lip/pDNA ternary complex. The CASF/Lip/pDNA complex was transfected into lung cancer cells A549 to investigate the transfection efficiency, the PLK1 gene knockout effect and the inhibitory effect on lung cancer cells. The results showed that the transfection efficiency of the CASF/Lip/pDNA complex was significantly higher than that of the Lip/pDNA binary complex, and the expression of PLK1 in cells transfected with CASF/Lip/pDNA complexes was significantly lower than that in cells transfected with Lip/pDNA complexes. The CASF/Lip/pDNA complex significantly increased the apoptosis rate and decreased the proliferation activity of lung cancer cells compared with Lip/pDNA complexes. The cytotoxicity of the complexes was evaluated by coculture with the human bronchial epithelial cells BEAS2B. The results showed that CASF/Lip/pDNA complexes exhibited lower cytotoxicity than Lip/pDNA complexes. The fibroin-modified liposome/PLK1 gene knockout system not only effectively inhibited the growth of lung cancer cells but also showed no obvious toxicity to normal cells, showing potential for clinical application in lung cancer therapy. [ABSTRACT FROM AUTHOR]

Ebselen is a glutathione (GSH) peroxidase (GPx) mimic originally developed to reduce reactive oxygen species (ROS). However, little is known about its cytotoxicological effects on lung cells. Therefore, this study aimed to investigate the effects of Ebselen on the cell growth and cell death of A549 lung cancer cells, Calu-6 lung cancer cells, and primary normal human pulmonary fibroblast (HPF) cells in relation to redox status. The results showed that Ebselen inhibited the growth of A549, Calu-6, and HPF cells with IC50 values of approximately 12.5 μM, 10 μM, and 20 μM, respectively, at 24 h. After exposure to 15 μM Ebselen, the proportions of annexin V-positive cells were approximately 25%, 65%, and 10% in A549, Calu-6, and HPF cells, respectively. In addition, Ebselen induced arrest at the S phase of the cell cycle in A549 cells and induced G2/M phase arrest in Calu-6 cells. Treatment with Ebselen induced mitochondrial membrane potential (MMP; ΔΨm) loss in A549 and Calu-6 cells. Z-VAD, a pan-caspase inhibitor, did not decrease the number of annexin V-positive cells in Ebselen-treated A549 and Calu-6 cells. Intracellular ROS levels were not significantly changed in the Ebselen-treated cancer cells at 24 h, but GSH depletion was efficiently induced in these cells. Z-VAD did not affect ROS levels or GSH depletion in Ebselen-treated A549 or Ebselen-treated Calu-6 cells. In conclusion, Ebselen inhibited the growth of lung cancer and normal fibroblast cells and induced cell cycle arrest and cell death in lung cancer cells with GSH depletion. [ABSTRACT FROM AUTHOR]

Despite the well-described anticarcinogenic effects of endocannabinoids, the influence of the endocannabinoid system on tumor angiogenesis is still debated. In the present study, conditioned medium (CM) from A549 and H358 lung cancer cells treated with ascending concentrations of the monoacylglycerol lipase (MAGL) inhibitor JZL184 and 2-arachidonoylglycerol (2-AG), a prominent MAGL substrate, caused a concentration-dependent reduction in human umbilical vein endothelial cell (HUVEC) migration and tube formation compared with CM from vehicle-treated cancer cells. Comparative experiments with MAGL inhibitors JW651 and MJN110 showed the same results. On the other hand, the angiogenic properties of HUVECs were not significantly altered by direct stimulation with JZL184 or 2-AG or by exposure to CM of JZL184- or 2-AG-treated non-cancerous bronchial epithelial cells (BEAS-2B). Inhibition of HUVEC migration and tube formation by CM of JZL184- and 2-AG-treated A549 cells was abolished in the presence of the CB1 antagonist AM-251. Increased release of tissue inhibitor of metalloproteinase-1 (TIMP-1) from JZL184- or 2-AG-stimulated A549 or H358 cells was shown to exert an antiangiogenic effect on HUVECs, as confirmed by siRNA experiments. In addition, JZL184 caused a dose-dependent regression of A549 tumor xenografts in athymic nude mice, which was associated with a decreased number of CD31-positive cells and upregulation of TIMP-1-positive cells in xenograft tissue. In conclusion, our data suggest that elevation of 2-AG by MAGL inhibition leads to increased release of TIMP-1 from lung cancer cells, which mediates an antiangiogenic effect on endothelial cells. [ABSTRACT FROM AUTHOR]

Plasma technology has recently been one of the potential candidates for the targeted treatment of cancers. In this work, Nightingale®, a non-thermal air plasma jet device, was used to activate lactated Ringer's injection (LRI) for the in vitro inactivation of lung cancer cells—A549 and H1299. The optimal treatment condition and its effects on the cell cytotoxicity of lung cancer cells were evaluated. Optical emission spectroscopy (OES) and gas detection results indicated gas phase reactive oxygen and nitrogen species (RONS) can be controlled and precisely calculated from plasma dissipated power. For plasma-activated LRI (PA-LRI), concentrations of H2O2, NO3−, and NO2−, as well as their shelf lives, were investigated. Two-hour treatment of PA-LRI on A549 and H1299 cells resulted in 92% and 70% cell death, respectively. While the non-cancerous cell, human lung fibroblast (HLF), was not affected neither in terms of cell death or morphological change. To elucidate the mechanisms of the tumor cell cytotoxicity induced by PA-LRI, common active species generated in PA-LRI (H2O2, NO2−, NO3−) were tested. Results showed that H2O2 alone can induce 72% of cell death, compared to PA-LRI, while it was 19% and 2% for NO2− and NO3− respectively. The addition of catalase, which degrades H2O2, reduced cell death induced by PA-LRI and H2O2 to 9% and 6%, respectively. These suggest H2O2 is the main player in PA-LRI-induced lung cancer cell death in vitro. Our discoveries not only benefit the effective usage of plasma-activated LRI but also the applications of plasma technology in medical fields. [ABSTRACT FROM AUTHOR]

Hypochlorous acid (HOCl) is an essential signal molecule in cancer cells. Activated GRP78 ATPase by a HOCl probe named ZBM-H inhibits lung cancer cell growth. However, the role and underlying mechanism of GRP78 ATPase in lung cancer cell migration have not been established. Here, we reported that activation of GRP78 ATPase by ZBM-H suppressed A549 cell migration and inhibited EMT process. Notably, ZBM-H time-dependently decreased the protein level of integrin β4 (ITGB4) in A549 cells. Combinatorial treatment of 3BDO (an autophagy inhibitor) and ZBM-H partially rescued the protein level of ITGB4. Consistently, 3BDO partially reversed ZBM-H-inhibited cell migration. Furthermore, ZBM-H promoted the interaction between ANXA7 and Hsc70, which participated in the regulation of selective autophagy and degradation of ITGB4.

In the antioxidant system in cyanobacteria, non-enzymatic antioxidants, such as carotenoids, are considered good candidates for coping with oxidative stress, particularly light stress, and pharmaceutical therapeutic applications. A significant amount of carotenoid accumulation has been recently improved by genetic engineering. In this study, to achieve higher carotenoid production with higher antioxidant activity, we successfully constructed five Synechocystis sp. PCC 6803 strains overexpressing (OX) native genes related to the carotenoids biosynthetic pathway, including OX_CrtB, OX_CrtP, OX_CrtQ, OX_CrtO, and OX_CrtR. All of the engineered strains maintained a significant quantity of myxoxanthophyll, while increasing zeaxanthin and echinenone accumulation. In addition, higher components of zeaxanthin and echinenone were noted in all OX strains, ranging from 14 to 19% and from 17 to 22%, respectively. It is worth noting that the enhanced echinenone component responded to low light conditions, while the increased β-carotene component contributed to a high light stress response. According to the higher antioxidant activity of all OX strains, the carotenoid extracts presented lower IC50 in lung cancer cell lines H460 and A549, with values less than 157 and 139 µg/mL, respectively, when compared with those of WTc, particularly OX_CrtR and OX_CrtQ. A higher proportion of zeaxanthin and β-carotene in OX_CrtR and OX_CrtQ, respectively, may considerably contribute to the ability to treat lung cancer cells with antiproliferative and cytotoxic effects. [ABSTRACT FROM AUTHOR]

Objective To explore the molecular mechanism of arginine methyltransferase 1（CARM1）regulating ferroptosis in malignant biology of lung cancer cells. Methods The expression of CARM1 in normal human bronchial epithelial cells（HBE4）and lung cancer lines（A549, H1299, H1640, HCC827）was detected by western blot. CARM1 sequence or Vector and shRNA sequence against CARM1（shCARM1）and Notch homologue 2 （shNotch2）or negative control shRNA（shNC）were transfected into lung cancer cells. Cell proliferation, migration and invasion were measured by CCK-8 test and Transwell test respectively. RIP-PCR and MeRIP-qPCR analysis were used to explore the mechanism of CARM1. Erastin, a classical ferroptosis inducer, was used to treat lung cancer cells to determine whether CARM1 could affect the sensitivity of cells to ferroptosis. Results Compared with human normal airway epithelial cell HBE4, CARM1 was significantly over-expressed in lung cancer lines（A549, H1299, H1640, HCC827）（P < 0.05）. Compared with Vector group, the proliferation, migration and invasion ability of A549 cells in CARM1 group was significantly increased（P < 0.001）, while that of HCC827 cells in shCARM1 group was significantly lower than that in shNC group（P < 0.001）. MeRIP-qPCR analysis showed that m6A abundance of Notch2 mRNA increased significantly when CARM1 was overexpressed（P < 0.05）. RIP analysis showed that CARM1 overexpression significantly promoted the binding between CARM1 and Notch2 mRNA （P < 0.05）. Notch2 knockdown weakened the proliferation, invasion and migration of A549 cells up-regulated by CARM1（P < 0.001）. Conclusion CARM1 is significantly elevated in lung cancer, and plays its carcinogenic role by activating Notch2. In addition, CARM1 can make lung cancer cells insensitive to ferroptosis by stabilizing Notch2. [ABSTRACT FROM AUTHOR]

A new series of nanostructured materials was obtained by functionalization of SBA-15 mesoporous silica with Ru(II) and Ru(III) complexes bearing Schiff base ligands derived from salicylaldehyde and various amines (1,2-diaminocyclohexane, 1,2-phenylenediamine, ethylenediamine, 1,3-diamino-2-propanol, N,N-dimethylethylenediamine, 2-aminomethyl-pyridine, and 2-(2-aminoethyl)-pyridine). The incorporation of ruthenium complexes into the porous structure of SBA-15 and the structural, morphological, and textural features of the resulting nanostructured materials were investigated by FTIR, XPS, TG/DTA, zeta potential, SEM, and N2 physisorption. The ruthenium complex-loaded SBA-15 silica samples were tested against A549 lung tumor cells and MRC-5 normal lung fibroblasts. A dose-dependent effect was observed, with the highest antitumoral efficiency being recorded for the material containing [Ru(Salen)(PPh3)Cl] (50%/90% decrease in the A549 cells' viability at a concentration of 70 μg/mL/200 μg/mL after 24 h incubation). The other hybrid materials have also shown good cytotoxicity against cancer cells, depending on the ligand included in the ruthenium complex. The antibacterial assay revealed an inhibitory effect for all samples, the most active being those containing [Ru(Salen)(PPh3)Cl], [Ru(Saldiam)(PPh3)Cl], and [Ru(Salaepy)(PPh3)Cl], especially against Staphylococcus aureus and Enterococcus faecalis Gram-positive strains. In conclusion, these nanostructured hybrid materials could represent valuable tools for the development of multi-pharmacologically active compounds with antiproliferative, antibacterial, and antibiofilm activity. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is a common cancer with high incidence and mortality rates. In recent years, ginsenoside Rg3 (Rg3), a traditional medicine, is widely used for the treatment of LC. Herein, we concentrate on assessing the effect of Rg3 on LC cell migration and invasion. The effects of Rg3 (0, 25, 50, and 100 μg/ml) on the viability, migration, invasion, angiogenesis, and expressions of epithelial–mesenchymal transition (EMT)‐related proteins, cyclooxygenase‐2 (COX2), and vascular endothelial growth factor (VEGF) of LC cell lines were evaluated by cell counting kit‐8 (CCK‐8), scratch, transwell, tube formation, and western blot assays. Quantitative real‐time polymerase chain reaction (qRT‐PCR) was performed to assess transfection efficiency. COX2 overexpression plasmid and short hairpin RNA for VEGF (shVEGF) were applied to evaluate whether the effect of Rg3 is related to COX2 and VEGF through rescue assay. In this study, Rg3 significantly dose‐dependently suppressed the viability, migration, invasion, angiogenesis, and protein expressions of N‐cadherin, vimentin, COX2, and VEGF in H1299 and A549 cells, while promoting the expression of E‐cadherin protein. COX2 overexpression markedly reversed the effects of Rg3 on the viability, migration, invasion, angiogenesis, and EMT‐related protein expression levels in LC cells; however, such effects of COX2 overexpression were offset by VEGF knockdown. In sum, Rg3 alleviates the migration, invasion, and angiogenesis of LC cells by inhibiting the expressions of COX2 and VEGF. [ABSTRACT FROM AUTHOR]

Background: TAB182 is overexpressed in cancerous tissues and correlated with poor overall survival in lung cancer patients. Mechanistically, TAB182 participates in DNA damage repair and endows tumour cells with radio- and chemoresistance. However, its role in non-small cell lung cancer (NSCLC) remains unclear. Methods and results: Cells with stable TAB182 knockdown (KD) were generated using A549 NSCLC cells, and we demonstrated that depleting TAB182 inhibits cell EMT, proliferation, colony formation, migration and invasion. Analysis of the TCGA database showed a positive correlation between TAB182 and EGFR, a well-established NSCLC oncoprotein. Then, we verified that silencing TAB182 decreases EGFR expression at both the mRNA and protein levels. Moreover, both TAB182 and EGFR were reported to restore ionizing radiation (IR)-triggered DNA damage. We validated that IR elevates the protein level of EGFR and that silencing TAB182 can alleviate IR-induced EGFR upregulation. Furthermore, overexpressing EGFR abrogates the inhibitory effects of TAB182 KD on EMT, migration, and invasion in A549 cells. Conclusions: Our data demonstrated that EGFR expression is regulated by TAB182 and downregulation of TAB182 has a novel function to repress EMT, migration and invasion by decreasing EGFR, indicating TAB182 could regulate the malignant progression of NSCLC. [ABSTRACT FROM AUTHOR]

This study demonstrated the effective reduction of graphene oxide (GO) by employing thiourea as a reducing and stabilizing agent. Two fungi (Aspergillus flavus and Aspergillus fumigatus) were used for anti-fungal assay. Cell viability, cell cycle analysis, DNA fragmentation, and cell morphology were assessed to determine the toxicity of thiourea-reduced graphene oxide (T-rGO) on human lung cancer cells. The results revealed that GO and T-rGO were hazardous to cells in a dose-dependent trend. The viability of both A. fumigatus and A. flavus was affected by GO and T-rGO. The reactive oxygen species produced by T-rGO caused the death of A. flavus and A. fumigatus cells. This study highlighted the effectiveness of T-rGO as an antifungal agent. In addition, T-rGO was found to be more harmful to cancer cells than GO. Thus, T-rGO manifested great potential in biological and biomedical applications. [ABSTRACT FROM AUTHOR]

Background. Almost all cells are capable of secreting exosomes (Exos) for intercellular communication and regulation. Therefore, Exos can be used as a natural therapeutic platform to regulate genes or deliver drugs to treat diseases. M1 macrophages inhibit tumor growth by releasing pro-inflammatory factors. This study explored the applicability of M1 macrophage exosomes (M1-Exos) as gene carriers and the effects on GNG5 protein, and further examined whether macrophage repolarization could inhibit tumor activity. Methods. M0 macrophages were polarized toward M1 using vitexin. Exos were obtained from M1 macrophages by ultra-centrifugation. The transwell non-contact co-culture system was used to co-culture M1 macrophages with HLF-α human lung epithelial cells or A549 or H1299 lung cancer cells. MTT, scratch, and transwell assays were used to detect the cell viability, migration, and invasion ability of cells in the four groups. Flow cytometry was used to detect the apoptosis rate of each group, and western blot (WB) analysis was performed to detect the change in the expression of proliferation- and apoptosis-related proteins. We screened the differentially expressed microRNAs using quantitative polymerase chain reaction technology. Luciferase reporter analysis was performed to explore the interaction between miRNA and protein. We used Xenografted A549 tumors in nude mice to study the effect of M1-Exos on tumor cell growth in vivo. Results. The results showed that, under the M1 macrophage co-culture system, lung cancer cell viability, invasion, and migration ability decreased, and the number of apoptotic cells increased, will all indicators being statistically significant (P < 0:05). The expression levels of PCNA, KI67, and Bcl-2 decreased significantly, but that of Bax increased (P < 0:05). Exosomes can have the same effect on tumor cells as M1 macrophages. Exosomes can transport miR-let-7b-5p to tumor cells, and miR-let-7b-5p can inhibit tumor cell proliferation and promote tumor cell apoptosis by regulating the GNG5 protein level. Conclusions. M1-Exos inhibit the proliferation, invasion, and metastasis of lung cancer cells through miRNA-let-7b-5p and GNG5 signaling pathways and inhibit the anti-apoptotic ability of lung cancer cells. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study reports a microfluidic chip for generating a shear stress gradient. • A shear stress gradient is generated perpendicular to the medium flow. • NIH3T3 cells do not migrate directionally under a gradient of 0.015 Pa/mm. • CL1-5 cells show preferences for higher shear stress environments. • CL1-5 cells align parallel to the medium flow. Cells respond not only to biological regulatory factors but also to physical stimuli such as electric fields, light, and shear stress in their environment. These stimuli can lead to cell migration and morphological changes. In the human body, cells encounter fluid shear stress induced by interstitial flow, lymphatic flow, blood flow, or organ-specific conditions within their micro-environments. Therefore, fluid shear stress, a classic mechanical force, has gained significant attention in wound healing and cancer metastasis. In this study, a microfluidic chip was developed to both culture cells and generate a shear stress gradient to direct cell migration. The design of this device's geometry allows the generation of a shear stress gradient perpendicular to the direction of medium flow. This greatly eliminates the influence of flow-induced cell responses. Using mouse fibroblast cells (NIH3T3) and human lung cancer cells (CL1-5) as models, their migration directionality, migration rates, and alignment in response to the shear stress gradient were investigated. Within the stress range of 0.095–0.155 Pa and a gradient of 0.015 Pa/mm, NIH3T3 cells did not exhibit significant directional migration, differences in migration rates, or specific alignment patterns. In contrast, CL1-5 cells preferred higher shear stress environments and alignment parallel to the medium flow, suggesting that these conditions could induce higher mobility in these cancer cells. [ABSTRACT FROM AUTHOR]

Polo-like protein kinase 1 (PLK1) plays a key role in lung cancer cell mitosis. The knockout of PLK1 gene by the CRISPR–Cas9 system can effectively inhibit the proliferation of tumor cells, but there is no suitable vector for in vivo delivery. In this study, CRISPR–Cas9 gene knockout plasmids encoding sgRNA, Cas9 and green fluorescent protein were constructed. Then, the plasmids were packaged with liposome (Lip) and cholesterol-modified Antheraea pernyi silk fibroin (CASF) to obtain the CASF/Lip/pDNA ternary complex. The CASF/Lip/pDNA complex was transfected into lung cancer cells A549 to investigate the transfection efficiency, the PLK1 gene knockout effect and the inhibitory effect on lung cancer cells. The results showed that the transfection efficiency of the CASF/Lip/pDNA complex was significantly higher than that of the Lip/pDNA binary complex, and the expression of PLK1 in cells transfected with CASF/Lip/pDNA complexes was significantly lower than that in cells transfected with Lip/pDNA complexes. The CASF/Lip/pDNA complex significantly increased the apoptosis rate and decreased the proliferation activity of lung cancer cells compared with Lip/pDNA complexes. The cytotoxicity of the complexes was evaluated by coculture with the human bronchial epithelial cells BEAS2B. The results showed that CASF/Lip/pDNA complexes exhibited lower cytotoxicity than Lip/pDNA complexes. The fibroin-modified liposome/PLK1 gene knockout system not only effectively inhibited the growth of lung cancer cells but also showed no obvious toxicity to normal cells, showing potential for clinical application in lung cancer therapy.

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable, cell-permeable redox-cycling nitroxide water-soluble superoxide dismutase (SOD) mimetic agent. However, little is known about its cytotoxic effects on lung-related cells. Thus, the present study investigated the effects of Tempol on cell growth and death as well as changes in reactive oxygen species (ROS) and glutathione (GSH) levels in Calu-6 and A549 lung cancer cells, normal lung WI-38 VA-13 cells, and primary pulmonary fibroblast cells. Results showed that Tempol (0.5~4 mM) dose-dependently inhibited the growth of lung cancer and normal cells with an IC50 of approximately 1~2 mM at 48 h. Tempol induced apoptosis in lung cells with loss of mitochondrial membrane potential (MMP; ∆Ψm) and activation of caspase-3. There was no significant difference in susceptibility to Tempol between lung cancer and normal cells. Z-VAD, a pan-caspase inhibitor, significantly decreased the number of annexin V-positive cells in Tempol-treated Calu-6, A549, and WI-38 VA-13 cells. A 2 mM concentration of Tempol increased ROS levels, including O2•− in A549 and WI-38 VA-13 cells after 48 h, and specifically increased O2•− levels in Calu-6 cells. In addition, Tempol increased the number of GSH-depleted cells in Calu-6, A549, and WI-38 VA-13 cells at 48 h. Z-VAD partially downregulated O2•− levels and GSH depletion in Tempol-treated these cells. In conclusion, treatment with Tempol inhibited the growth of both lung cancer and normal cells via apoptosis and/or necrosis, which was correlated with increased O2•− levels and GSH depletion. [ABSTRACT FROM AUTHOR]

Core/shell gold "raspberry" nanostructures capable of multiple therapeutic functionalities were synthesized using a template composed of monodispersed anionic protein (bovine serum albumin) nanoparticles coated with a cationic biopolymer (poly-l-lysine). The nanostructures exhibited high photothermal conversion efficiency when exposed to a near-infrared (NIR) laser, which led to significant cellular inhibition of A549 human lung cancer cells due to intracellular hyperthermia. The raspberry structures also provided hot spots for surface-enhanced Raman scattering (SERS) ratiometric sensing of intracellular reactive oxygen species (ROS) when modified with the Raman reporter molecule 4-aminothiophenol (4-ATP). ROS was detected in A549 lung cancer cells upon photothermal heating of internalized nanostructures, enabling a possible mechanism for feedback on therapeutic efficacy. This was confirmed by adding the antioxidant N-acetylcysteine (NAC) and using a complementary fluorescence technique, which showed that the amount of detectable intracellular ROS decreased. These safe-by-design gold raspberry nanostructures could be promising for simultaneous therapeutic applications and monitoring therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Lung cancer is one of the leading forms of cancer in developed countries. Interleukin-8 (IL-8), a pro-inflammatory cytokine, exerts relevant effects in cancer growth and progression, including angiogenesis and metastasis in lung cancer. Mesoporous silica particles, functionalized with newly extracted fish oil (Omeg@Silica), are more effective than the fish oil alone in anti-proliferative and pro-apoptotic effects in non-small cell lung cancer (NSCLC) cell lines. The mechanisms that explain this efficacy are not yet understood. The aim of the present study is therefore to decipher the anti-cancer effects of a formulation of Omeg@Silica in aqueous ethanol (FOS) in adenocarcinoma (A549) and muco-epidermoid (NCI-H292) lung cancer cells, evaluating cell migration, as well as IL-8, NF-κB, and miRNA-21 expression. Results show that in both cell lines, FOS was more efficient than oil alone, in decreasing cell migration and IL-8 gene expression. FOS reduced IL-8 protein release in both cell lines, but this effect was only stronger than the oil alone in A549. In A549, FOS was able to reduce miRNA-21 and transcription factor NF-κB nuclear expression. Taken together, these data support the potential use of the Omeg@Silica as an add-on therapy for NSCLC. Dedicated studies which prove clinical efficacy are needed. [ABSTRACT FROM AUTHOR]

Background: Tumor hypoxia is a feature of tumor micro-environment (TME), which provides a suitable environment for tumor cells migration and invasion. However, up to now, the function of exosomes derived from hypoxic tumor cells is still not fully understood. The present study is aimed to explore the underlying mechanisms of lung cancer-secreted exosomes-mediated tumor metastasis under hypoxia. Methods & Results: Exosomes were isolated from normoxic or hypoxic NCI-H446 cells. Some characteristic proteins were detected by western blots. Levels of CD63, CD 9 and CD 81 proteins were up-regulated on the membrane of exosomes secreted by hypoxic NCI-H446 cells. Basing on the results from miRNA sequencing, qRT-PCR and wound healing assay, hsa-miR-625-3p was discovered to be accumulated inside hypoxic exosomes and responsible for the metastasis of lung cancer cell. Further experiments from luciferase reporter gene assay demonstrated hsa-miR-625-3p could directly inhibit SCAI expression through binding with its 3'UTR, which suggested the mechanisms by which exosomal hsa-miR-625-3p suppressed tumor cells migration. Conclusions: Exosomal miR-625-3p derived from hypoxic small lung cancer cells accelerated tumor cells migration through inhibiting SCAI directly. [ABSTRACT FROM AUTHOR]

Ebselen is a glutathione (GSH) peroxidase (GPx) mimic originally developed to reduce reactive oxygen species (ROS). However, little is known about its cytotoxicological effects on lung cells. Therefore, this study aimed to investigate the effects of Ebselen on the cell growth and cell death of A549 lung cancer cells, Calu-6 lung cancer cells, and primary normal human pulmonary fibroblast (HPF) cells in relation to redox status. The results showed that Ebselen inhibited the growth of A549, Calu-6, and HPF cells with IC50 values of approximately 12.5 μM, 10 μM, and 20 μM, respectively, at 24 h. After exposure to 15 μM Ebselen, the proportions of annexin V-positive cells were approximately 25%, 65%, and 10% in A549, Calu-6, and HPF cells, respectively. In addition, Ebselen induced arrest at the S phase of the cell cycle in A549 cells and induced G2/M phase arrest in Calu-6 cells. Treatment with Ebselen induced mitochondrial membrane potential (MMP; ΔΨm) loss in A549 and Calu-6 cells. Z-VAD, a pan-caspase inhibitor, did not decrease the number of annexin V-positive cells in Ebselen-treated A549 and Calu-6 cells. Intracellular ROS levels were not significantly changed in the Ebselen-treated cancer cells at 24 h, but GSH depletion was efficiently induced in these cells. Z-VAD did not affect ROS levels or GSH depletion in Ebselen-treated A549 or Ebselen-treated Calu-6 cells. In conclusion, Ebselen inhibited the growth of lung cancer and normal fibroblast cells and induced cell cycle arrest and cell death in lung cancer cells with GSH depletion.

Resveratrol is a naturally occurring polyphenol which has various beneficial effects, such as anti-inflammatory, anti-tumor, anti-aging, antioxidant, and neuroprotective effects, among others. The anti-cancer activity of resveratrol has been related to alterations in sphingolipid metabolism. We analyzed the effect of resveratrol on the enzymes responsible for accumulation of the two sphingolipids with highest functional activity—apoptosis promoting ceramide (CER) and proliferation-stimulating sphingosine-1-phosphate (S1P)—in human lung adenocarcinoma A549 cells. Resveratrol treatment induced an increase in CER and sphingosine (SPH) and a decrease in sphingomyelin (SM) and S1P. Our results showed that the most common mode of CER accumulation, through sphingomyelinase-induced hydrolysis of SM, was not responsible for a CER increase despite the reduction in SM in A549 plasma membranes. However, both the activity and the expression of CER synthase 6 were upregulated in resveratrol-treated cells, implying that CER was accumulated as a result of stimulated de novo synthesis. Furthermore, the enzyme responsible for CER hydrolysis, alkaline ceramidase, was not altered, suggesting that it was not related to changes in the CER level. The enzyme maintaining the balance between apoptosis and proliferation, sphingosine kinase 1 (SK1), was downregulated, and its expression was reduced, resulting in a decrease in S1P levels in resveratrol-treated lung adenocarcinoma cells. In addition, incubation of resveratrol-treated A549 cells with the SK1 inhibitors DMS and fingolimod additionally downregulated SK1 without affecting its expression. The present studies provide information concerning the biochemical processes underlying the influence of resveratrol on sphingolipid metabolism in A549 lung cancer cells and reveal possibilities for combined use of polyphenols with specific anti-proliferative agents that could serve as the basis for the development of complex therapeutic strategies. [ABSTRACT FROM AUTHOR]

Lamins are nuclear envelope proteins involved in various cellular functions, such as DNA modulation, cellular differentiation, and development. In this study, we investigate the role of histamine in lung cancer biology. Since it is known that lamin-A/C is negatively regulated in lung cancer, we hypothesize that histamine signaling is related to nuclear lamin-A/C regulation and cancer progression. Our findings reveal that histamine stimulation enhances lamin-A/C expression in lung cancer cells. Lamin-A/C expression is dependent on histamine-mediated intracellular calcium signaling and subsequent calcium/calmodulin-dependent kinase II (Ca/CaMKII) activation. The nuclear protein nestin, which stabilizes lamin-A/C expression, is also modulated by Ca/CaMKII. However, histamine-mediated lamin-A/C expression is independent of Akt/focal adhesion kinase or autophagy signaling. Histamine stimulation attenuates lung cancer motility in the presence of enhanced lamin-A/C expression. In conclusion, we propose a regulatory mechanism that accounts for the modulation of lamin-A/C levels through the involvement of Ca/CaMKII in cancer cells and provides molecular evidence of histamine signaling in lamin-A/C biology. [ABSTRACT FROM AUTHOR]

Study on the biological activity of compounds consisting only of the C/D ring of vitamin D has been very limited. We found that a synthetic C/D ring alcohol 3 reduced the viability of HeLa cells. Compound 3 was more active than vitamin D2 (VD2) against solid cancer cell lines HeLa and A549 (1 day incubation) and was a little weaker than VD2 against blood cancer cell lines KMS-12-PE and MT-2. Compound 3 rapidly induced cell killing in A549 cells. This compound was compared with staurosporine and it seemed to have a different mechanism of cell killing. Compound 3 did not show clear cytotoxicity to confluent cells that have terminated proliferation, indicating that the activity can be observed only when cells are proliferating. Furthermore, 3 induced cell death, possibly cytotoxicity, in A549 cells (at least 64%). This is the first example of vitamin D C/D ring derivative that kills cancer cells. [ABSTRACT FROM AUTHOR]

Sesamol has moved into biomedical research in recent years. However, its interactions with blood proteins and cancer cells have not been fully explored. Therefore, we aimed to investigate the interaction of sesamol with human serum albumin (HSA), A549 human nonsmall cell lung cancer (NSCLC) cell line, and Raw 264.7 macrophage. The interaction of HSA with sesamol was explored via application of fluorescence and circular dichroism (CD) spectroscopy studies as well as molecular docking analysis. Then, the cytotoxic effects of sesamol on A549 lung cancer cells and Raw 264.7 macrophages were evaluated by qPCR analysis. It was found that sesamol spontaneously (ΔG˚=-45.89 kJ/mol) binds with HSA having a high affinity (log Kb = 8.05, n = 1.70, T = 298 K) and form a static complex trough contribution of hydrogen bonds and van der Waals interactions (ΔH˚=-409.43 kJ/mol, TΔS˚=-363.54 kJ/mol) which was supported by molecular docking study. Furthermore, by using CD and synchronous fluorescence spectroscopy analyses it was found that sesamol induced some minor secondary and tertiary structural changes, respectively in HSA structure. Cellular assays displayed that sesamol triggered selective cytotoxicity against A549 lung cancer cells through regulation of intrinsic apoptosis pathway mediated by mitigation of mitochondrial membrane potential, elevation of ROS generation, downregulation of Bax, and up regulation of caspase-9, −3. In conclusion, it was found that sesamol could show high affinity with HSA and mediate intrinsic apoptosis pathway through ROS generation in the A549 lung cancer cell lines. These data indicate that the biochemical and anticancer mechanisms of sesamol can be further investigated in future studies to integrate it in the biomedical platforms.

Background and purpose: Epithelial-to-mesenchymal transition (EMT) is the key biological process of tumor cell metastasis. Blocking EMT inhibits tumor metastasis, therefore it is of great significance to elucidate the molecular mechanism of EMT. Tumor suppressor protein H2AX regulates apoptosis-related gene expression of tumor cells, and then produces anti-tumor effect. This study aimed to reveal the relationship between H2AX and EMT, and to explore the possible mechanism of H2AX regulating EMT in lung cancer cells. Methods: About 5% fetal bovine serum was used to induce EMT in lung cancer A549 stable cells including H2AX gene silencing, H2AX overexpression and H2AX phosphorylation site mutation. Western blot and real- time fluorescent quantitative polymerase chain reaction (RTFQ-PCR) were used to detect the expressions of E-cadherin, vimentin, vascular endothelial growth factor receptor 2 (VEGFR2) and other EMT-related proteins. Transwell experiment was used to analyze the migration and invasion of A549 cells. Results: Knockdown of H2AX in lung cancer A549 cells resulted in the downregulation of E-cadherin and the upregulation of vimentin, and enhanced the migration and invasion ability of A549 cells. Overexpression of H2AX in lung cancer A549 cells upregulated E-cadherin, downregulated vimentin, and inhibited the migration and invasion of A549 cells. Mutation of H2AX phosphorylation site eliminated the regulation of E-cadherin and vimentin by H2AX, and the inhibition of EMT by H2AX. H2AX knockdown in A549 cells stimulated the expression of VEGFR2, while overexpression of H2AX inhibited VEGFR2 expression. Mutation of H2AX phosphorylation site eliminated the VEGFR2 expression inhibition caused by H2AX. Knockdown of VEGFR2 inhibited the EMT of A549. Knockdown of H2AX stimulated the expression of EMT-related factors Slug and β-catenin, whereas overexpression of H2AX inhibited the expression of Slug and β-catenin. Reducing H2AX phosphorylation eliminated the expression inhibition of Slug and β-catenin by H2AX. Conclusion: H2AX inhibits EMT of lung cancer A549 cells by downregulating the expressions of VEGFR2, Slug and β-catenin.

Despite the well-described anticarcinogenic effects of endocannabinoids, the influence of the endocannabinoid system on tumor angiogenesis is still debated. In the present study, conditioned medium (CM) from A549 and H358 lung cancer cells treated with ascending concentrations of the monoacylglycerol lipase (MAGL) inhibitor JZL184 and 2-arachidonoylglycerol (2-AG), a prominent MAGL substrate, caused a concentration-dependent reduction in human umbilical vein endothelial cell (HUVEC) migration and tube formation compared with CM from vehicle-treated cancer cells. Comparative experiments with MAGL inhibitors JW651 and MJN110 showed the same results. On the other hand, the angiogenic properties of HUVECs were not significantly altered by direct stimulation with JZL184 or 2-AG or by exposure to CM of JZL184- or 2-AG-treated non-cancerous bronchial epithelial cells (BEAS-2B). Inhibition of HUVEC migration and tube formation by CM of JZL184- and 2-AG-treated A549 cells was abolished in the presence of the CB1 antagonist AM-251. Increased release of tissue inhibitor of metalloproteinase-1 (TIMP-1) from JZL184- or 2-AG-stimulated A549 or H358 cells was shown to exert an antiangiogenic effect on HUVECs, as confirmed by siRNA experiments. In addition, JZL184 caused a dose-dependent regression of A549 tumor xenografts in athymic nude mice, which was associated with a decreased number of CD31-positive cells and upregulation of TIMP-1-positive cells in xenograft tissue. In conclusion, our data suggest that elevation of 2-AG by MAGL inhibition leads to increased release of TIMP-1 from lung cancer cells, which mediates an antiangiogenic effect on endothelial cells.

A new series of nanostructured materials was obtained by functionalization of SBA-15 mesoporous silica with Ru(II) and Ru(III) complexes bearing Schiff base ligands derived from salicylaldehyde and various amines (1,2-diaminocyclohexane, 1,2-phenylenediamine, ethylenediamine, 1,3-diamino-2-propanol, N,N-dimethylethylenediamine, 2-aminomethyl-pyridine, and 2-(2-aminoethyl)-pyridine). The incorporation of ruthenium complexes into the porous structure of SBA-15 and the structural, morphological, and textural features of the resulting nanostructured materials were investigated by FTIR, XPS, TG/DTA, zeta potential, SEM, and N2 physisorption. The ruthenium complex-loaded SBA-15 silica samples were tested against A549 lung tumor cells and MRC-5 normal lung fibroblasts. A dose-dependent effect was observed, with the highest antitumoral efficiency being recorded for the material containing [Ru(Salen)(PPh3)Cl] (50%/90% decrease in the A549 cells’ viability at a concentration of 70 μg/mL/200 μg/mL after 24 h incubation). The other hybrid materials have also shown good cytotoxicity against cancer cells, depending on the ligand included in the ruthenium complex. The antibacterial assay revealed an inhibitory effect for all samples, the most active being those containing [Ru(Salen)(PPh3)Cl], [Ru(Saldiam)(PPh3)Cl], and [Ru(Salaepy)(PPh3)Cl], especially against Staphylococcus aureus and Enterococcus faecalis Gram-positive strains. In conclusion, these nanostructured hybrid materials could represent valuable tools for the development of multi-pharmacologically active compounds with antiproliferative, antibacterial, and antibiofilm activity.

Baicalin plays important roles in different types of cancer. A previous report showed that baicalin attenuates cisplatin resistance in lung cancer. However, its mechanism remains unclear. In this study, we investigated the effect and mechanism of baicalin on DNA repair and sensitivity of lung cancer cells to cisplatin. A549 and A549/DPP cells were treated with baicalin and cisplatin. A549/DPP cells were transfected with XRCC1 and siXRCC1. Cell viability and DNA damage were detected by MTT and comet assay. Apoptosis rate and cell cycle were detected by flow cytometry assay. The expressions of Bax, Bcl-2, and Cyclin D1 were detected by western blot. XRCC1 expression was detected by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot. Baicalin and cisplatin decreased cell viability in A549 and A549/DPP cells in dose-dependent manner. Baicalin enhanced the effect of cisplatin on promoting apoptosis, arresting cell on S stage and triggering DNA damage accompanied with the upregulation of Bcl-2-associated X protein (Bax) and downregulation of B-cell lymphoma 2 (Bcl-2) and Cyclin D1 in A549/DPP cells. Moreover, baicalin promoted the inhibitory effect of cisplatin on XRCC1 expression in A549 and A549/DPP cells. However, the synthetic effects of baicalin and cisplatin on A549/DPP cells were partially inhibited by XRCC1 overexpression and promoted by XRCC1 knockdown. This study demonstrates that baicalin interferes with XRCC1-mediated cellar DNA repair to sensitize lung cancer cells to cisplatin. [ABSTRACT FROM AUTHOR]

Background: Lung cancer (LC) is the most common types of cancer worldwide and is marked by high mortality rate. LC is classified into two major types due to their molecular and histological properties; non-small cell lung cancer (NSCLC) A549 and small cell lung cancer (SCLC). Currently, surgery, chemotherapy and radiation therapy are the most common treatment options of LC. However, the survival rate of LC is still very poor. Therefore, new treatment strategies are urgently needed. Erufosine (ErPC3) is a novel alkylphosphocholine and inhibits the translocation of Akt to the plasma membrane. Methods and results: In the current study, the effects of ErPC3 in NSCLC cell line A549 and SCLC cell line DMS 114 in terms of cell viability, induction of apoptosis, cell cycle phase distribution, gene and protein expression levels, and migration capacity were investigated. 25 µM ErPC3 exhibited dose-dependent cytotoxicity against in both cancer cells. However, DMS 114 was more sensitive to ErPC3 than A549. Similarly, ErPC3 induced apoptotic cell ratio in DMS114 was significantly greater than A549. 25 µM ErPC3 caused the accumulation of both cell in G2/M phase. The levels of BCL-2 were downregulated and CASPASE 3–7 and BAX were upregulated while p-Akt levels were reduced in A549 and DMS 114 cells treated with 25 µM ErPC3. Besides, ErPC3 displayed anti-migratory effect on A549 and DMS 114. Conclusion: These findings suggest that ErPC3 may be a promising novel therapeutic candidate for treatment of LC. ErPC3 treatment merits further investigation as potential agent against LC. [ABSTRACT FROM AUTHOR]

Summary: Background One of the main challenges in the clinical treatment of lung cancer is resistance to chemotherapeutic drugs. P-glycoprotein (P-gp)-mediated drug resistance is the main obstacle to successfully implementing microtubule-targeted tumor chemotherapy. Purpose In this study, we explored the effect of Ad-hTERTp-E1a-Apoptin (Ad-VT) on drug-resistant cell lines and the molecular mechanism by which Ad-VT combined with chemotherapy affects drug-resistant cells and parental cells. Methods In vitro, cell proliferation, colony formation, resistance index (RI), apoptosis and autophagy assays were performed. Protein expression was analyzed by Western blotting. Finally, a xenograft tumor model in nude mice was used to detect tumor growth and evaluate histological characteristics. Results Our results showed that Ad-VT had an obvious killing effect on A549, A549/GEM and A549/Paclitaxel cancer cells, and the sensitivity of drug-resistant cell lines to Ad-VT was significantly higher than that of parental A549 cells. Compared with A549 cells, A549/GEM and A549/Paclitaxel cells had higher autophagy levels and higher viral replication ability. Ad-VT decreased the levels of p-PI3k, p-Akt and p-mTOR and the expression of P-gp. In vivo, Ad-VT combined with chemotherapy can effectively inhibit the growth of chemotherapy-resistant tumors and prolong the survival of mice. Conclusions Thus, the combination of Ad-VT and chemotherapeutic drugs will be a promising strategy to overcome chemoresistance. [ABSTRACT FROM AUTHOR]

Abstract Background Lung cancer is one of the leading causes of death worldwide due to its strong proliferative and metastatic capabilities. The suppression of these aggressive behaviors is of interest in anticancer drug research and discovery. In recent years, many plants have been explored in order to discover new bioactive secondary metabolites to treat cancers or enhance treatment efficiency. Aspiletrein A (AA) is a steroidal saponin isolated from the whole endemic species Aspidistra letreae in Vietnam. Previously, elucidation of the structure of AA and screening of its cytotoxic activity against several cancer cell lines were reported. However, the antitumor activities and mechanisms of action have not yet been elucidated. In this study, we demonstrated the anti-proliferative, anti-migrative and anti-invasive effects of AA on H460, H23 and A549 human lung cancer cells. Methods MTT, wound healing and Transwell invasion assays were used to evaluate the anti-proliferation, anti-migration and anti-invasion effects of AA, respectively. Moreover, the inhibitory effect of AA on the activity of protein kinase B (Akt), a central mediator of cancer properties, and apoptotic regulators in the Bcl-2 family proteins were investigated by Western blotting. Results AA exhibits antimetastatic effects in human lung cancer cells through the inhibition of the pAkt/Akt signaling pathway, which in turn resulted in a significant inhibitory effect of AA on the migration and invasion of the examined lung cancer cells. Conclusions Aspiletrein A may be a potent inhibitor of protein kinase B (Akt). Hence, AA could be further explored as a potential antimetastatic lead compound.

Abstract Background Lung cancer is one of the most frequently diagnosed cancers all over the world and is also one of the leading causes of cancer-related mortality. The main treatment option for small cell lung cancer, conventional chemotherapy, is characterized by a lack of specificity, resulting in severe adverse effects. Therefore, this study aimed at developing a new targeted drug delivery (TDD) system based on Ag–In–Zn–S quantum dots (QDs). For this purpose, the QD nanocrystals were modified with 11-mercaptoundecanoic acid (MUA), L-cysteine, and lipoic acid decorated with folic acid (FA) and used as a novel TDD system for targeting doxorubicin (DOX) to folate receptors (FARs) on adenocarcinomic human alveolar basal epithelial cells (A549). NIH/3T3 cells were used as FAR-negative controls. Comprehensive physicochemical, cytotoxicity, and genotoxicity studies were performed to characterize the developed novel TDDs. Results Fourier transformation infrared spectroscopy, dynamic light scattering, and fluorescence quenching confirmed the successful attachment of FA to the QD nanocrystals and of DOX to the QD–FA nanocarriers. UV–Vis analysis helped in determining the amount of FA and DOX covalently anchored to the surface of the QD nanocrystals. Biological screening revealed that the QD–FA–DOX nanoconjugates had higher cytotoxicity in comparison to the other forms of synthesized QD samples, suggesting the cytotoxic effect of DOX liberated from the QD constructs. Contrary to the QD–MUA–FA–DOX nanoconjugates which occurred to be the most cytotoxic against A549 cells among others, no such effect was observed for NIH/3T3 cells, confirming FARs as molecular targets. In vitro scratch assay also revealed significant inhibition of A549 cell migration after treatment with QD–MUA–FA–DOX. The performed studies evidenced that at IC 50 all the nanoconjugates induced significantly more DNA breaks than that observed in nontreated cells. Overall, the QD–MUA–FA–DOX nanoconjugates showed the greatest cytotoxicity and genotoxicity, while significantly inhibiting the migratory potential of A549 cells. Conclusion QD–MUA–FA–DOX nanoconjugates can thus be considered as a potential drug delivery system for the effective treatment of adenocarcinomic human alveolar basal epithelial cells.

Abstract Background Understanding the signalling pathways involved in angiogenesis, and developing anti-angiogenic drugs are one of the major focuses on cancer research. Herein, we assessed the effect of CPTH6, a lysine acetyltransferase inhibitor and anti-tumoral compound, on angiogenesis-related properties of both endothelial and cancer cells. Methods The in vitro effect of CPTH6 on protein acetylation and anti-angiogenic properties on endothelial and lung cancer cells was evaluated via wound healing, trans-well invasion and migration, tube formation, immunoblotting and immunofluorescence. Matrigel plug assay, zebrafish embryo and mouse xenograft models were used to evaluate in vivo anti-angiogenic effect of CPTH6. Results CPTH6 impaired in vitro endothelial angiogenesis-related functions, and decreased the in vivo vascularization both in mice xenografts and zebrafish embryos. Mechanistically, CPTH6 reduced α-tubulin acetylation and induced accumulation of acetylated microtubules in the perinuclear region of endothelial cells. Interestingly, CPTH6 also affected the angiogenesis-related properties of lung cancer cells, and conditioned media derived from CPTH6-treated lung cancer cells impaired endothelial cells morphogenesis. CPTH6 also modulated the VEGF/VEGFR2 pathway, and reshaped cytoskeletal organization of lung cancer cells. Finally, anti-migratory effect of CPTH6, dependent on α-tubulin acetylation, was also demonstrated by genetic approaches in lung cancer cells. Conclusion Overall, this study indicates that α-tubulin acetylation could play a role in the anti-angiogenic effect of CPTH6 and, more in general, it adds information to the role of histone acetyltransferases in tumor angiogenesis, and proposes the inhibition of these enzymes as an antiangiogenic therapy of cancer.

This study demonstrated the effective reduction of graphene oxide (GO) by employing thiourea as a reducing and stabilizing agent. Two fungi (Aspergillus flavus and Aspergillus fumigatus) were used for anti-fungal assay. Cell viability, cell cycle analysis, DNA fragmentation, and cell morphology were assessed to determine the toxicity of thiourea-reduced graphene oxide (T-rGO) on human lung cancer cells. The results revealed that GO and T-rGO were hazardous to cells in a dose-dependent trend. The viability of both A. fumigatus and A. flavus was affected by GO and T-rGO. The reactive oxygen species produced by T-rGO caused the death of A. flavus and A. fumigatus cells. This study highlighted the effectiveness of T-rGO as an antifungal agent. In addition, T-rGO was found to be more harmful to cancer cells than GO. Thus, T-rGO manifested great potential in biological and biomedical applications.

Tempol (4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl) is a stable, cell-permeable redox-cycling nitroxide water-soluble superoxide dismutase (SOD) mimetic agent. However, little is known about its cytotoxic effects on lung-related cells. Thus, the present study investigated the effects of Tempol on cell growth and death as well as changes in reactive oxygen species (ROS) and glutathione (GSH) levels in Calu-6 and A549 lung cancer cells, normal lung WI-38 VA-13 cells, and primary pulmonary fibroblast cells. Results showed that Tempol (0.5~4 mM) dose-dependently inhibited the growth of lung cancer and normal cells with an IC50 of approximately 1~2 mM at 48 h. Tempol induced apoptosis in lung cells with loss of mitochondrial membrane potential (MMP; ∆Ψm) and activation of caspase-3. There was no significant difference in susceptibility to Tempol between lung cancer and normal cells. Z-VAD, a pan-caspase inhibitor, significantly decreased the number of annexin V-positive cells in Tempol-treated Calu-6, A549, and WI-38 VA-13 cells. A 2 mM concentration of Tempol increased ROS levels, including O2•− in A549 and WI-38 VA-13 cells after 48 h, and specifically increased O2•− levels in Calu-6 cells. In addition, Tempol increased the number of GSH-depleted cells in Calu-6, A549, and WI-38 VA-13 cells at 48 h. Z-VAD partially downregulated O2•− levels and GSH depletion in Tempol-treated these cells. In conclusion, treatment with Tempol inhibited the growth of both lung cancer and normal cells via apoptosis and/or necrosis, which was correlated with increased O2•− levels and GSH depletion.

Lung cancer is one of the leading forms of cancer in developed countries. Interleukin-8 (IL-8), a pro-inflammatory cytokine, exerts relevant effects in cancer growth and progression, including angiogenesis and metastasis in lung cancer. Mesoporous silica particles, functionalized with newly extracted fish oil (Omeg@Silica), are more effective than the fish oil alone in anti-proliferative and pro-apoptotic effects in non-small cell lung cancer (NSCLC) cell lines. The mechanisms that explain this efficacy are not yet understood. The aim of the present study is therefore to decipher the anti-cancer effects of a formulation of Omeg@Silica in aqueous ethanol (FOS) in adenocarcinoma (A549) and muco-epidermoid (NCI-H292) lung cancer cells, evaluating cell migration, as well as IL-8, NF-κB, and miRNA-21 expression. Results show that in both cell lines, FOS was more efficient than oil alone, in decreasing cell migration and IL-8 gene expression. FOS reduced IL-8 protein release in both cell lines, but this effect was only stronger than the oil alone in A549. In A549, FOS was able to reduce miRNA-21 and transcription factor NF-κB nuclear expression. Taken together, these data support the potential use of the Omeg@Silica as an add-on therapy for NSCLC. Dedicated studies which prove clinical efficacy are needed.

Terrein is a fungal metabolite that has already been reported with anticancer properties. However, the effect on the aggressive phenotype of cancer cells has not been elucidated yet. In the present study, the cytotoxicity of terrein was first determined against lung cancer cells (A549) model and compared with several normal cell lines (Vero, L6, and H9C2 cells). The data demonstrated that terrein had a specific effect on A549 cells relative to normal cells with high selectivity index values. Then, the hypoxic model that recognized to induce aggressive abilities was established in A549 cells by cobalt chloride (CoCl2) stimulation. With this model, terrein could reduce HIF-1α, a marker of hypoxia, and inhibit both migration and invasion of which the effect on invasion is more explicit. Our results demonstrated that terrein has a potential new role as the anti-aggressive phenotype by inhibiting cancer cell migration and invasion through HIF-1α reduction. [ABSTRACT FROM AUTHOR]

Cardiac glycosides (CGs) are useful drugs to treat cardiac illnesses and have potent cytotoxic and anticancer effects in cultured cells and animal models. Their receptor is the Na+,K+ ATPase, but other plasma membrane proteins might bind CGs as well. Herein, we evaluated the short- and long-lasting cytotoxic effects of the natural cardenolide glucoevatromonoside (GEV) on non-small-cell lung cancer H460 cells. We also tested GEV effects on Na+,K+ -ATPase activity and membrane currents, alone or in combination with selected chemotherapy drugs. GEV reduced viability, migration, and invasion of H460 cells spheroids. It also induced cell cycle arrest and death and reduced the clonogenic survival and cumulative population doubling. GEV inhibited Na+,K+-ATPase activity on A549 and H460 cells and purified pig kidney cells membrane. However, it showed no activity on the human red blood cell plasma membrane. Additionally, GEV triggered a Cl-mediated conductance on H460 cells without affecting the transient voltage-gated sodium current. The administration of GEV in combination with the chemotherapeutic drugs paclitaxel (PAC), cisplatin (CIS), irinotecan (IRI), and etoposide (ETO) showed synergistic antiproliferative effects, especially when combined with GEV + CIS and GEV + PAC. Taken together, our results demonstrate that GEV is a potential drug for cancer therapy because it reduces lung cancer H460 cell viability, migration, and invasion. Our results also reveal a link between the Na+,K+-ATPase and Cl- ion channels. [ABSTRACT FROM AUTHOR]

Toxicarioside O (TCO), a natural product derived from Antiaris toxicaria, has been identified to be a promising anticancer agent. In this study, we aimed to investigate the effect of TCO on the proliferation and epithelial-mesenchymal transition (EMT) of lung cancer cells and its molecular mechanisms. Here, we indicated that TCO inhibits the proliferation of lung cancer cells both in vitro and in vivo. Our results demonstrated that TCO induces apoptosis in lung cancer cells. Moreover, we found that TCO suppresses EMT program and inhibits cell migration in vitro. Mechanistically, TCO decreases the expression of trophoblast cell surface antigen 2 (Trop2), resulting in inhibition of the PI3K/Akt pathway and EMT program. Overexpression of Trop2 rescues TCO-induced inhibition of cell proliferation and EMT. Our findings demonstrate that TCO markedly inhibits cell proliferation and EMT in lung cancer cells and provides guidance for its drug development.