Inhibits Lung Cancer Growth Research Articles

Glutathione inhibits lung cancer development by reducing interleukin-6 expression and reversing the Warburg effect

Reduced glutathione (GSH) is widely used as an antioxidant in clinical practice, but whether GSH affects the development of early lung cancer remains unclear. Herein, we investigated the mechanism underlying the anticancer effect of GSH in patients with pulmonary nodules. Thirty patients with pulmonary nodules were treated with GSH intravenously for 10 days at a dose of 1.8 g/d, followed by oral administration of the drug at a dose of 0.4 g three times daily for 6 months. The results showed that GSH treatment promoted nodule absorption and reduced the IL-6 level in the peripheral blood of the patients. GSH reduced IL-6 expression in inflammatory BEAS-2B and lung cancer cells and inhibited the proliferation of lung cancer cell lines in vitro. In addition, GSH reduced IL-6 expression by decreasing ROS via down-regulating PI3K/AKT/FoxO pathways. Finally, GSH reversed the Warburg effect, restored mitochondrial function, and reduced the IL-6 expression via PI3K/AKT/FoxO pathways. The in vivo experiment confirmed that GSH inhibited lung cancer growth, improved mitochondrial function, and reduced the IL-6 expression by regulating key enzymes via the PI3K/AKT/FoxO pathway. In conclusion, we uncovered that GSH exerts an unprecedentedly potent anti-cancer effect to prevent the transformation of lung nodules to lung cancer by improving the mitochondrial function and suppressing inflammation via PI3K/AKT/FoxO pathway. This investigation innovatively positions GSH as a potentially safe and efficacious old drug with new uses, inhibiting inflammation and early lung cancer. The use of the drug offers a promising preventive strategy when administered during the early stages of lung cancer.

Scutellarein inhibits lung cancer growth by inducing cell apoptosis and inhibiting glutamine metabolic pathway

Ethnopharmacological relevanceScutellaria baicalensis Georgi, a widely used Chinese medicinal herb, has shown effectiveness against lung cancer. Scutellarein, a key component of Scutellaria baicalensis, also demonstrates anticancer properties in lung cancer. However, the underlying mechanisms have not yet been clarified. Aim of the studyThis study aimed to investigate the effects of scutellarein in the treatment of NSCLC and its underlying mechanisms. MethodsThis study explored the effects of scutellarein on non–small cell lung cancer (NSCLC) and its mechanisms. A Lewis lung cancer mouse model was established to assess scutellarein's anticancer activity in vivo. Additionally, the compound's effects on cell proliferation, colony formation, migration, and apoptosis were evaluated in vitro using A549 and H1299 lung cancer cells. Metabolomics analysis was conducted to identify changes in cellular metabolism due to scutellarein, while molecular docking and western blotting techniques were employed to elucidate the molecular mechanisms of its anti-lung cancer effects. ResultsScutellarein significantly inhibited lung cancer xenograft tumor growth. In vitro studies showed that scutellarein suppressed migration and colony formation in A549 and H1299 cells, induced cell cycle arrest, and triggered cell apoptosis. Notably, scutellarein profoundly altered amino acid metabolism, particularly affecting glutamine metabolites. It affected key glutamine transporters ASCT2 and LAT1, as well as glutaminase GLS1, leading to their reduced expression. ConclusionScutellarein effectively inhibits lung cancer growth both in vivo and in vitro by inducing cell apoptosis and downregulating the glutamine metabolic pathway.

Isoquercitrin Inhibits Lung Cancer Cell Growth Through Triggering Pyroptosis and Ferroptosis

Isoquercitrin possesses anti-tumor activity in several types of cancers, however, its effects and underlying mechanisms on lung cancer have not been reported. Human lung cancer cell lines as well as normal lung epithelial BEAS-2B cells were treated with isoquercitrin. The influences of isoquercitrin in vitro were evaluated by determining cell viability, apoptosis, pyroptosis, and ferroptosis. Additionally, A549 tumor-bearing mice were generated to explore the anti-cancer effect of isoquercitrin in vivo. We found that isoquercitrin dose-dependently reduced lung cancer cells’ viability, with no toxicity against BEAS-2B cells. Isoquercitrin at 40 μM and 80 μM was used in vitro. Isoquercitrin increased apoptosis, elevated NLRP3 inflammasome activation-mediated pyroptosis, and promoted ferroptosis in lung cancer cells. NLRP3 knockdown and caspase-1 selective inhibitor VX-765 attenuated isoquercitrin-induced pyroptosis and ferroptosis, but not apoptosis. Furthermore, isoquercitrin accelerated ROS generation, while ROS inhibitor N-acetylcysteine abrogated isoquercitrin-induced apoptosis, NLRP3 related-pyroptosis and ferroptosis. In vivo, isoquercitrin (1 mg/kg and 5 mg/kg) inhibited tumor growth, increased apoptosis, NLRP3-related pyroptosis, ferroptosis and ROS generation in tumors. Taken together, isoquercitrin inhibits lung cancer growth by triggering ROS/NLRP3-mediated pyroptosis and ferroptosis, with ROS also directly inducing apoptosis. This suggests that isoquercitrin might be a potential therapeutic agent for lung cancer.

TRMT10C-mediated m7G modification of circFAM126A inhibits lung cancer growth by regulating cellular glycolysis

The N7-methylguanosine (m7G) modification and circular RNAs (circRNAs) have been shown to play important roles in the development of lung cancer. However, the m7G modification of circRNAs has not been fully elucidated. This study revealed the presence of the m7G modification in circFAM126A. We propose the novel hypothesis that the methyltransferase TRMT10C mediates the m7G modification of circFAM126A and that the stability of m7G-modified circFAM126A is reduced. circFAM126A is downregulated in lung cancer and significantly inhibits lung cancer growth both in vitro and in vivo. The expression of circFAM126A correlates with the stage of lung cancer and with the tumour diameter, and circFAM126A can be used as a potential molecular target for lung cancer. The molecular mechanism by which circFAM126A increases HSP90 ubiquitination and suppresses AKT1 expression to regulate cellular glycolysis, ultimately inhibiting the progression of lung cancer, is elucidated. This study not only broadens the knowledge regarding the expression and regulatory mode of circRNAs but also provides new insights into the molecular mechanisms that regulate tumour cell metabolism and affect tumour cell fate from an epigenetic perspective. These findings will facilitate the development of new strategies for lung cancer prevention and treatment.Graphical Graphical Headlights• circRNA can undergo m7G modification. The methyltransferase TRMT10C mediates circFAM126A m7G modification, thereby enhancing circFAM126A stability.• m7G-modified circFAM126A can perform a biological function in inhibiting lung cancer progression by regulating cellular glycolysis.• circFAM126A increases ubiquitination of HSP90 and inhibits AKT1 expression to regulate cellular glycolysis.

Scorpiones, Scolopendra and Gekko Inhibit Lung Cancer Growth and Metastasis by Ameliorating Hypoxic Tumor Microenvironment via PI3K/AKT/mTOR/HIF-1α Signaling Pathway.

To investigate whether Buthus martensii karsch (Scorpiones), Scolopendra subspinipes mutilans L. Koch (Scolopendra) and Gekko gecko Linnaeus (Gekko) could ameliorate the hypoxic tumor microenvironment and inhibit lung cancer growth and metastasis by regulating phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin/hypoxia-inducible factor-1α (PI3K/AKT/mTOR/HIF-1α) signaling pathway. Male C57BL/6J mice were inoculated with luciferase labeled LL/2-luc-M38 cell suspension to develop lung cancer models, with rapamycin and cyclophosphamide as positive controls. Carboxy methyl cellulose solutions of Scorpiones, Scolopendra and Gekko were administered intragastrically as 0.33, 0.33, and 0.83 g/kg, respectively once daily for 21 days. Fluorescent expression were detected every 7 days after inoculation, and tumor growth curves were plotted. Immunohistochemistry was performed to determine CD31 and HIF-1α expressions in tumor tissue and microvessel density (MVD) was analyzed. Western blot was performed to detect the expression of PI3K/AKT/mTOR/HIF-1α signaling pathway-related proteins. Enzyme-linked immunosorbent assay was performed to detect serum basic fibroblast growth factor (bFGF), transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF) in mice. Scorpiones, Scolopendra and Gekko prolonged the survival time and inhibited lung cancer metastasis and expression of HIF-1α (all P<0.01). Moreover, Scorpiones, Scolopendra and Gekko inhibited the phosphorylation of AKT and ribosomal protein S6 kinase (p70S6K) (P<0.05 or P<0.01). In addition, they also decreased the expression of CD31, MVD, bFGF, TGF-β1 and VEGF compared with the model group (P<0.05 or P<0.01). Scorpiones, Scolopendra and Gekko all showed beneficial effects on lung cancer by ameliorating the hypoxic tumor microenvironment via PI3K/AKT/mTOR/HIF-1α signaling pathway.

Abstract CT252: Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial

Abstract Background: RUNX3 is a tumor suppressor gene, which is inactivated in approximately 70% of lung adenocarcinomas. Nicotinamide, a sirtuin inhibitor, has demonstrated potential in re-activating epigenetically silenced RUNX3 in cancer cells. This study assessed the therapeutic benefits of combining nicotinamide with first-generation EGFR-TKIs for patients with stage IV lung cancer carrying EGFR mutations. Patients and Methods: We assessed the impact of nicotinamide on carcinogen-induced lung adenocarcinomas in mice and observed that nicotinamide increased RUNX3 levels and inhibited lung cancer growth. Subsequently, 110 consecutive patients with stage IV lung cancer who had EGFR mutations were recruited: 70 females (63.6%) and 84 never-smokers (76.4%). The patients were randomly assigned to receive either nicotinamide (1 g/day, n = 55) or placebo (n = 55). The primary and secondary endpoints were progression-free survival (PFS) and overall survival (OS), respectively. Results: After a median follow-up of 54.3 months, the nicotinamide group exhibited a median PFS of 12.7 months (95% CI, 10.4-18.3), while the placebo group had a PFS of 10.9 months (9.0-13.2; p = 0.2). The median OS was similar in the two groups (31.0 months with nicotinamide vs. 29.4 months with placebo; p = 0.2). Notably, subgroup analyses revealed a significant reduction in mortality risk for females (p = 0.01) and never-smokers (p = 0.03) treated with nicotinamide. Conclusion: The addition of nicotinamide with EGFR-TKIs demonstrated potential improvements in PFS and OS, with notable survival benefits for female patients and those who had never smoked. (ClinicalTrials.gov Identifier: NCT02416739) Citation Format: Cheol-Kyu Park, Hyung-Joo Oh, Suk-Chul Bae, In-Jae Oh, Kyoung-Mi Jung, Da-Mi Kim, Jung-Won Lee, Chang Kyun Kang, Il Yeong Park, Young-Chul Kim. Nicotinamide in combination with EGFR-TKIs for the treatment of stage IV lung adenocarcinoma with EGFR mutations: A randomized double-blind (Phase IIb) trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT252.

Diterpenoid Tanshinones Can Inhibit Lung Cancer Progression by Improving the Tumor Microenvironment and Downregulation of NF-κB Expression.

Diterpenoid tanshinones (DTs) are a bioactive fraction extracted from Salvia miltiorrhiza. High-performance liquid chromatography analysis revealed the presence of four compounds, namely, tanshinone IIA, tanshinone I, cryptotanshinone, and dihydrotanshinone. In this study, we aimed to propose a possible mechanism for the anti-lung cancer effect of DT. To do so, we utilized a lung cancer nude mice model and a lung cancer cell line (PC9) to investigate the effect of DT on lung cancer. We employed immunohistochemistry, enzyme-linked immunosorbent assay, hematoxylin and eosin staining, and immunofluorescence to analyze the pharmacological role of DT in the inhibition of lung cancer growth. The results showed that DT inhibited tumor growth, induced apoptosis in the nude mice model, and reduced inflammatory cell infiltration. Additionally, DT inhibited PC9 lung cancer cells, growth, proliferation, and migration. The mechanism of action of DT involves not only directly inhibiting cell proliferation and migration but also improving the tumor microenvironment. DT significantly increased the expression of important intestinal gap junction proteins, such as zonula occludens 1 (ZO-1) and occludin I. This upregulation contributes to the reinforcement of the intestinal mucosal barrier, thereby reducing the paracellular transport of lipopolysaccharides (LPS) through the intestine. Consequently, the decreased LPS levels lead to the inhibition of NF-κB expression and downregulation of macrophage polarization, as indicated by the decreased expression of CD68. In conclusion, this study has confirmed that DT has anti-lung cancer properties by improving the inflammatory tumor microenvironment via regulating macrophage polarization and inhibiting LPS-associated immune response. These results provide new insights into the mechanism of DT action against lung cancer.

Lnc AC016727.1/BACH1/HIF-1 α signal loop promotes the progression of non-small cell lung cancer

BackgroundLong noncoding RNAs (lncRNAs) have been reported to play vital roles in the development and progression of cancer. However, their biological significance and functional mechanisms in non-small cell lung cancer (NSCLC) are mostly unclear.MethodsWe performed RNA-sequencing to predict the differential expression of lncRNAs in clinical NSCLC and paired paracancerous lung tissues. To identify lncRNA expression, quantitative polymerase chain reaction (qPCR) was used. Using both cell and mouse models, We studied lncRNA AC016727.1’s function in NSCLC growth and metastasis. Western blot assays, dual luciferase reporter assays, and chromatin immunoprecipitation were used to analyze the functional mechanism of lncRNA AC016727.1.ResultsOur larger NSCLC cohorts validated that the lncRNA AC016727.1 was upregulated in 94 paired NSCLC tissues and correlated with poor survival. Functionally, lncRNA AC016727.1 downregulation inhibited NSCLC cell proliferation, aerobic glycolysis, EMT, and migration, inducing apoptosis. Conversely, upregulated lncRNA AC016727.1 expression exhibited the opposite effect, promoting NSCLC cell survival. Importantly, lncRNA AC016727.1 knockdown inhibited lung cancer growth and slowed the progression of lung metastasis in nude mouse models. Mechanistically, lncRNA AC016727.1 upregulated BACH1 target gene expression by acting as a sponge for miR-98-5p, thereby functioning as a competing endogenous RNA. The function of lncRNA AC016727.1 is mediated by the miR-98-5p/BACH1 axis in NSCLC cells. Meanwhile, the transcription factor HIF-1α can bind to the promoter and activate lncRNA AC016727.1 transcription. lncRNA AC016727.1 regulates HIF-1α expression via BACH1 in NSCLC and forms the lncRNA AC016727.1/BACH1/HIF-1α signaling loop under hypoxic conditions.ConclusionOur study reveals a novel lncRNA AC016727.1/BACH1/HIF-1α signaling loop in the progression of NSCLC under hypoxic conditions, suggesting that lncRNA AC016727.1 could act as a useful biomarker for NSCLC and a new therapeutic target.

A novel CD47-blocking peptide fused to pro-apoptotic KLA repeat inhibits lung cancer growth in mice.

CD47 is highly expressed in many tumor tissues and induces immune evasion by interaction with SIRP-alpha (signal regulatory protein-alpha) expressed on tumor-associated macrophages. In this study, we identified a novel CD47-blocking peptide VK17 by phage display technique. A pro-apoptotic VK30 peptide was obtained after VK17 was fused to KLA amino acid repeat at C-termini. The VK30 was specifically bound to CD47 on lung cancer cells, and subsequently inducing lung cancer cell apoptosis. Meanwhile, the expression of Bax was increased, whereas the expression of Bcl-2 and Ki-67 were reduced in the VK30-treated lung cancer cells. In addition, VK30 effectively improved the phagocytic activity of macrophages against VK30-pretreated lung cancer cells. Combinational treatment of lung cancer cells with blocking antibody anti-CD47 and VK30 additively enhanced VK30 binding to CD47, subsequently increasing lung cancer cell apoptosis and macrophage phagocytosis. Intraperitoneal administration of 2mg/kg VK30 induced effective trafficking of VK30 into tumor tissues, and suppressing lung cancer cell growth in mice, associated with increased tumor cell apoptosis, macrophage activation and phagocytosis in vivo. The expression of CD47 was reduced in the VK30-treated tumor tissues and the expression level was positively correlated to tumor size. In addition, VK30 reduced the infiltration of CD11b+Ly6G+ neutrophils and CD11b+Ly6C+Ly6G+ granulocytic myeloid-derived suppressor cells (Gr-MDSCs) in tumor tissues, associated with suppressed expression of tumorigenic IL-6 and TNF-alpha from these cell types. Thereby, VK30 exerted anti-tumor effects in mice through inducing tumor cell apoptosis and macrophage phagocytosis. VK30 would be a novel therapeutic peptide in lung cancer immunotherapy.

Anti-tumor effects of novel alkannin derivatives with potent selectivity on comprehensive analysis

BackgroundTherapeutic approaches based on glycolysis and energy metabolism of tumor cells are new promising strategies for the treatment of cancer. Currently, researches on the inhibition of pyruvate kinase M2, a key rate limiting enzyme in glycolysis, have been corroborated as an effective cancer therapy. Alkannin is a potent pyruvate kinase M2 inhibitor. However, its non-selective cytotoxicity has affected its subsequent clinical application. Thus, it needs to be structurally modified to develop novel derivatives with high selectivity. PurposeOur study aimed to ameliorate the toxicity of alkannin through structural modification and elucidate the mechanism of the superior derivative 23 in lung cancer therapy. MethodsOn the basis of the principle of collocation, different amino acids and oxygen-containing heterocycles were introduced into the hydroxyl group of the alkannin side chain. We examined the cell viability of all derivatives on three tumor cells (HepG2, A549 and HCT116) and two normal cells (L02 and MDCK) by MTT assay. Besides, the effect of derivative 23 on the morphology of A549 cells as observed by Giemsa and DAPI staining, respectively. Flow cytometry was performed to assess the effects of derivative 23 on apoptosis and cell cycle arrest. To further assess the effect of derivative 23 on the Pyruvate kinase M2 in glycolysis, an enzyme activity assay and western blot assay were performed. Finally, in vivo the antitumor activity and safety of the derivative 23 were evaluated by using Lewis mouse lung cancer xenograft model. ResultsTwenty-three novel alkannin derivatives were designed and synthesized to improve the cytotoxicity selectivity. Among these derivatives, derivative 23 showed the highest cytotoxicity selectivity between cancer and normal cells. The anti-proliferative activity of derivative 23 on A549 cells (IC50 = 1.67 ± 0.34 μM) was 10-fold higher than L02 cells (IC50 = 16.77 ± 1.44 μM) and 5-fold higher than MDCK cells (IC50 = 9.23 ± 0.29 μM) respectively. Subsequently, fluorescent staining and flow cytometric analysis showed that derivative 23 was able to induce apoptosis of A549 cells and arrest the cell cycle in the G0/G1 phase. In addition, the mechanistic studies suggested derivative 23 was an inhibitor of pyruvate kinase; it could regulate glycolysis by inhibiting the activation of the phosphorylation of PKM2/STAT3 signaling pathway. Furthermore, studies in vivo demonstrated derivative 23 significantly inhibited the growth of xenograft tumor. ConclusionIn this study, alkannin selectivity is reported to be significantly improved following structural modification, and derivative 23 is first shown to be able to inhibit lung cancer growth via the PKM2/STAT3 phosphorylation signaling pathway in vitro, indicating the potential value of derivative 23 in treating lung cancer.

Ebracteolatain A Inhibits Lung Cancer Growth via p21 and p27 Mediated Cell-Cycle Arrest

Objective: Lung cancer is a refractory tumor with a poor five-year survival rate. Ebracteolatain A (EA), a key acetyl-phloroglucinol derived from the traditional Chinese herb Langdu, has been reported to have anti-tumor activity in human breast cancer. However, the therapeutic efficacy and underlying mechanism of lung cancer remain to be elucidated. In the present study, we intended to evaluate whether EA exhibits anti-lung cancer activity and elucidate the underlying mechanisms. Methods: ATPlite and clonogenic survival assays were used to assess the inhibiting effect of EA on two lung cancer cell lines in vitro. FACS was conducted to determine the cell-cycle profiling of lung cancer cells upon treatment with EA. Western blot was performed to detect the level of related proteins in EA-treated lung cancer cells. RNA silencing and other experiments were used to identify the molecular mechanism of EA-triggered cell-cycle arrest. Furthermore, a xenograft tumor model was constructed to evaluate the therapeutic effect and potential mechanism of EA in vivo in mice. Results: EA significantly inhibited the growth of lung cancer cells both in vitro and in vivo. Mechanistically, EA-induced G1 phase cell-cycle arrest is mediated by the accumulation of p21 and p27. Conclusion: Our findings revealed the anti-lung cancer effect of EA and the mechanisms, providing a solid scientific basis for EA as an attractive choice for lung cancer therapy.

Abstract 1836: Combining a novel retinoic acid receptor-γ agonist with immune checkpoint blockade represses lung cancer growth in vivo

Abstract All-trans-retinoic acid (ATRA), a pan-agonist for retinoic acid receptors (RARs), regulates diverse cellular functions including growth, differentiation and immune function. We report here that ATRA-treatment represses tumor growth in syngeneic, immunocompetent but not in immunodeficient mice. Tumor immune microenvironment was implicated since depletion of cytotoxic T lymphocytes antagonized these effects in syngeneic mice. Combining ATRA with immune checkpoint blockade did not inhibit lung cancer growth in mice. We sought to augment retinoid anti-tumor effects without affecting its pro-tumorigenicity. We previously reported that CD38 mediated resistance to checkpoint blockade in murine 344SQ lung cancer cells via RARα transcriptional activation of CD38 expression. Yet, combining the RARα antagonist (IRX6696) with anti-PD-L1 did not augment anti-tumorigenicity in transplanted 344SQ cells in syngeneic mice. Prior work implicated RARγ in regulating T cell response. Combining the novel RARγ agonist (IRX4647) with anti-PD-L1 statistically-significantly repressed 344SQ lung cancer cell growth in syngeneic mice. This line is relatively resistant to checkpoint blockade. Immunofluorescent analysis of these treated tumors revealed that combined IRX4647 and anti-PD-L1 treatments reduced CD38 expression in the tumor stroma relative to IRX4647 or anti-PD-L1 treatment alone. Statistically-significantly elevated helper (CD4+) T cells were detected in treated tumors along with increased IL-5 and IL-13 expression observed in plasma and tumors. These cytokines can activate helper T cells, altering lung cancer growth. These microenvironment effects were associated with in vivo anti-tumorigenicity. IRX4647-treatment did not appreciably alter in vitro growth of lung cancer cells although retinoid receptors expression profiles were affected. Pharmacokinetic study of IRX4647 found its plasma half-life was 6 hours. Combining an RARγ agonist with immune checkpoint blockade exerted superior anti-neoplastic efficacy against lung cancer versus an ATRA-based regimen. Given these findings we propose exploring activity of this RARγ agonist with an optimal checkpoint inhibitor in a lung cancer clinical trial. Citation Format: Cheng-Hsin Wei, Lu Huang, Blair Kreh, Xiuxia Liu, Liliya Tyutyunyk-Massey, Zibo Chen, Mi Shi, Vidyasagar Vuligonda, Martin Sanders, Serguei Kozlov, King Chan, Amir Horowitz, Mary Carrington, Patrick Hwu, Weiyi Peng, Ethan Dmitrovsky, Xi Liu. Combining a novel retinoic acid receptor-γ agonist with immune checkpoint blockade represses lung cancer growth in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1836.

Organosulfur Compound Identified from Striga angustifolia (D. Don) C.J. Saldanha Inhibits Lung Cancer Growth and Induces Apoptosis via p53/mTOR Signaling Pathway.

The Striga angustifolia (D. Don) C.J. Saldanha was used as an Ayurvedic and homeopathic medicine for cancer by the tribal peoples of the Maruthamalai Hills, Coimbatore, India. Hence, the traditional use that has been proven to be effective lacks convincing scientific references. This present study was conducted to investigate the presence of potentially bioactive compounds from S. angustifolia and provides a scientific basis for the ethnobotanical utility. The organosulfur compound 5,5'-dithiobis(1-phenyl-1H-tetrazole) (COMP1) was isolated from S. angustifolia extracts, and the structures of COMP1 were elucidated and characterized by using 13C and 1H nuclear magnetic resonance (NMR) and single crystal X-ray powder diffraction (XRD). Our findings showed that COMP1 significantly reduced cell proliferation of breast and lung cancer cells, but not that of non-malignant epithelial cells. Further analysis revealed that COMP1 promoted cell cycle arrest and apoptosis of lung cancer cells. Mechanistically, COMP1 facilitates p53 activity and inhibits mammalian target of rapamycin (mTOR) signaling, thereby inducing cell cycle arrest and apoptosis of lung cancer cells by inhibiting cell growth. Our findings suggest that COMP1 may serve as a potential drug for lung cancer through the regulation of p53/mTOR pathways.

Bai He Gu Jin Tang (Lily Bulb Decoction to Preserve the Metal): A Chinese Herbal Medication for the Metal Element

Bai He Gu Jin Tang is one of the most commonly used herbal formulas to treat dry chronic cough from Lung and Kidney Yin Deficiencies. Deficiency of these two organs can develop from internal causes (chronic disease, chronic medication) or from external causes (exogenous Heat pathogen, dry/hot environment). This formula is effective for both conditions. Common conditions for which Bai He Gu Jin Tang may be used in veterinary medicine include: acute and chronic bronchitis from a variety of causes including aging, recovery from pneumonia/heartworm disease/kennel cough, chronic drug therapy, asthma, upper respiratory tract infection, spontaneous pneumothorax and cancer of the nose and lungs. In China, herbal medicine is commonly used to treat lung cancer in humans with Bai He Gu Jin Tang as one of the most commonly used herbal formulas. The mechanism of anti-neoplastic activity was investigated with positive results drawing the conclusion that the herbal formula inhibits lung cancer growth and represents a potential integrative treatment for lung cancer. Human clinical trials have also demonstrated the utility of the herbal formula (90% effective) for patients with chronic cough characterized by dryness and heat and successful treatment of pneumonia in humans when compared to conventional therapy.

Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin.

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.

Formosanin C inhibits non-small-cell lung cancer progression by blocking MCT4/CD147-mediated lactate export

BackgroundTumor cells reprogram their metabolic network to maintain their uncontrolled proliferation, metastasis, and resistance to cancer therapy. Treatments targeting abnormal cellular metabolism may have promising therapeutic effects. Formosanin C (FC), a diosgenin derived from the rhizoma of Paris polyphylla var. yunnanensis, has shown potent anti-cancer activities against various cancer types. However, the effect of FC on cancer metabolism remains to be elucidated. PurposeIn this research, we aimed to elucidate FC's effect and potential mechanisms on metabolism in lung cancer. MethodsColony formation, transwell cell migration, and apoptosis were detected in multiple NSCLC cell lines to assess the cytotoxicity of FC. 1H NMR metabolomics approach was applied to screen the differential metabolites in H1299 cells and the culture medium. Western blotting, flow cytometry, and other molecular biological techniques were performed to verify the latent mechanism involved in metabolites. An allograft tumor model was employed to investigate the anti-tumor effects of FC in vivo. ResultsFC significantly inhibited monoclonal formation and migration and induced cell cycle arrest and apoptosis in NSCLC cells. FC altered the abundances of 12 metabolites in lung cancer cells and 3 metabolites in the medium. These differential metabolites are primarily involved in glycolysis, citric acid cycle, and glutathione pathways. Notably, there was a remarkable increase in intracellular lactate and a reduction in extracellular lactate after FC treatment. Mechanically, FC downregulated the expression of MCT4 and CD147, blocking the export of lactate. Furthermore, FC also evoked mitochondrial dysfunction coupled with excessive oxidative stress, decreased mitochondrial membrane potential, ATP production reduction, glutathione depletion, and Ca2+ overload. Moreover, FC suppressed tumor progression in vivo with reduced protein levels of the MCT4 and CD147 in tumor tissues. ConclusionFC inhibits lung cancer growth by the novel mechanism in which MCT4/CD147-mediated inhibition of lactate transport and disruption of mitochondrial functions are involved.

Celastrol inhibits lung cancer growth by triggering histone acetylation and acting synergically with HDAC inhibitors

Alterations in histone modification have been linked to cancer development and progression. Celastrol, a Chinese herbal compound, shows potent anti-tumor effects through multiple signaling pathways. However, the involvement of histone modifications in this process has not yet been illustrated. In this study, barcode sequencing of a eukaryotic genome-wide deletion library revealed that histone modifications, especially histone acetylation associated with the NuA4 histone acetyltransferase complex, were involved in the anti-proliferation actions of celastrol. The essential roles of histone modification were verified by celastrol sensitivity tests in cells lacking specific genes, such as genes encoding the subunits of the NuA4 and Swr1 complex. The combination of celastrol and histone deacetylase inhibitors (HDACi), rather than the combination of celastrol and histone acetyltransferase inhibitors, synergistically suppressed cancer cell proliferation. In addition to upregulating H4K16 acetylation (H4K16ac), celastrol regulates H3K4 tri-methylation and H3S10 phosphorylation. Celastrol treatment significantly enhanced the suppressive effects of HDACi on lung cancer cell allografts in mice, with significant H4K16ac upregulation, indicating that a combination of celastrol and HDACi is a potential novel therapeutic approach for patients with lung cancer.

Novel matrinic acid derivatives bearing 2-anilinothiazole structure for non-small cell lung cancer treatment with improved Hsp90 targeting effect.

Involved in mediating the folding and maturation of more than 300 client proteins, many of which are oncoproteins, Hsp90 has emerged as a promising drug target for cancer therapy. In particular, inhibiting Hsp90 plays a vital role in the treatment of non-small cell lung cancer. Owing to undesirable outcomes of Hsp90 inhibitors in clinical trials, a series of matrinic acid compounds bearing 2-anilinothiazole moiety were designed based on the structural features allocation shared among Hsp90 inhibitors within the ATP-binding pocket. Most of the compounds showed potent anticancer activities validated by MTT assay. Amongthem, the most potent compound C4 (IC50 < 10 μM against four cell lines) was chosen for further mechanism study. Notably, C4 showed a better safety profile than 17AAG with a higher SI value. Thermal shift assay data indicated C4 exhibited a strong binding affinity with Hsp90 (-18.85 ± 0.56°C) comparable to radicicol. Mechanism studies verified that C4 significantly inhibited proliferation and migration activities of A549 cells. Besides, C4 can induce a prolonged G1-phase and cell apoptosis. Western blot analysis results indicated C4 could moderately suppress Hsp90 and upregulate Hsp70 expression. Furthermore, the downregulated trend of the client proteins of Hsp90, such as β-Catenin and Bcl-2, were consistent with the cellular effect of C4, suggesting that C4 could exert anticancer activity via targeting Hsp90. In the xenograft model in vivo, C4 effectively inhibited lung cancer growth without obvious side effects. Collectively, C4 could be a promising therapeutic agent for lung cancer and the novel scaffold provided new insights into the design of Hsp90 inhibitors.

Engineered Exosomes Loaded with miR-563 Inhibit Lung Cancer Growth.

The malignancy of lung cancer (LC) is serious in the world. Exosomes are well-known natural nanovesicles, which are reported to have the potential to carry functional miRNAs as natural carriers and deliver chemotherapeutic drugs. However, the safety and functions of the engineered exosomes for delivering miRNA for the treatment of LC remain to be evaluated. In this study, we found that miR-563 is related to lung cancer from GeneCard database. RT-qPCR and in situ hybridization (ISH) were used to assess miR-563 expression in clinical samples. We prepared and verified the engineered exosomes loaded with miR-563 both in vitro and in vivo. In vitro, flow cytometry, Western blot, and other experimental methods were performed to evaluate the antitumor effect of miR-563 loaded exosomes. In in vivo, the LC mouse model was used to observe the effect of the prepared exosomes. The safety of using this exosomes was accessed by liver function test, hematological analysis, and H&E staining in major organs of the mice. Our findings indicated that the miR-563 loaded engineered exosomes inhibit the A549 cells growth in vitro, by inhibiting the tumor cell proliferation, migration, and invasion and promoting apoptosis. In in vivo, these engineered exosomes were enriched in tumor tissue after injecting to LC model mice and impacted tumor tissue by inhibiting the tumor volume and tumor weight. Importantly, our study indicated that miR-563 loaded engineered exosomes have the potential for clinical application for LC treatment with acceptable safety profiles. Our findings indicate a novel potential therapeutic target for lung cancer patients by miR-563 loaded engineered exosomes.

Icariin inhibits the malignant progression of lung cancer by affecting the PI3K/Akt pathway through the miR‑205‑5p/PTEN axis.

Icariin (ICA) is one of the main bioactive monomer belonging to the flavonoid glycosides that has been widely studied in multiple diseases, including lung cancer. Although ICA has shown anticancer effects, its specific molecular mechanism of action remains to be elucidated. In the present study, the expression of microRNA (miR)-205-5p and Phosphatase and tensin homolog deleted on chromosome ten (PTEN) in human lung cancer and bronchial cells were analyzed. Cell viability, colony formation, migration, invasion, apoptosis and cell cycle distribution were investigated in vitro. In addition, the function of ICA on tumor growth was determined using a xenotransplantation model. The results showed that ICA decreased the viability of lung cancer cells. In addition, miR-205-5p was upregulated in lung cancer tissues but downregulated following ICA treatment, while PTEN showed a significantly lower expression in lung cancer cells. miR-205-5p could increase cancer cell proliferation, migration, invasion and cell cycle progression while suppressing cell apoptosis. Importantly, rescue experiment results showed that ICA could target the miR-205-5p/PTEN axis to affect the PI3K/Akt signaling, thereby suppressing the malignant cell phenotype of lung cancer. Finally, animal experiments confirmed that ICA could inhibit lung cancer growth in vivo. Taken together, our findings suggest that miR-205-5p is a key gene targeted by ICA to inhibit lung cancer progression.