Inhibits Lung Cancer Research Articles

Upregulation of phosphatase and tensin homolog deleted on chromosome ten inhibits lung cancer cell proliferation by suppressing the oncogene polo-like kinase 1 and inducing autophagy

Objective: Lung cancer is one of the main causes of cancer-related mortality globally, and it poses considerable therapeutic challenges. Polo-like kinase 1 (PLK1) exhibits upregulation in lung cancer, and PLK1 silencing promotes autophagy in lung cancer cells, which inhibits tumor progression. The phosphatase and tensin homolog deleted on chromosome ten (PTEN) acts as a tumor suppressor gene. This study aimed to investigate whether PTEN regulates autophagy and inhibits lung cancer-cell proliferation by suppressing PLK1. Material and Methods: In this study, we evaluated cell proliferation by silencing or overexpressing PLK1 and PTEN in A549 cells through 5-ethynyl-2'-deoxyuridine labeling and cloning experiments. The autophagy levels were detected through transmission electron microscopy, real-time quantitative polymerase chain reaction, and Western blot. Finally, the results of in vitro experiment were further verified using an in vivo xenograft tumor animal model. Results: The upregulation of PTEN suppressed PLK1 expression in lung cancer cells and reduced their proliferation rate. In addition, the overexpression of PTEN has been associated with the growth of lung cancer tumors. In parallel, the levels of autophagy of lung cancer cells rose in response to PTEN upregulation in vivo and in vitro. Conclusion: This study revealed that PTEN promotes the autophagy of lung cancer cells and inhibits cell proliferation and tumor growth by suppressing PLK1 expression. This finding provides a new strategy for lung cancer treatment by utilizing the autophagy-regulating effect of PTEN to inhibit lung cancer growth by targeting PLK1.

PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment

BackgroundMore efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a...

HMGB1 secretion by resveratrol in NSCLC: A pathway to ferroptosis-mediated platelet activation suppression.

Cancer-associated venous thromboembolism (CAT) is a frequent and serious complication in cancer patients. Resveratrol, a natural compound with reported anti-tumor effects, is not fully understood in its role regarding CAT in lung cancer. This study aims to explore resveratrol's potential to diminish platelet activation induced by lung adenocarcinoma cells and uncover the underlying mechanisms. Clinical data on coagulation function in non-small cell lung cancer (NSCLC) patients were gathered. A549 human lung cancer cells and Lewis mouse lung cancer cells were employed to assess tumor-induced platelet activation and the impact of resveratrol on this process. Western blotting analyzed protein expression, electron microscopy examined extracellular vesicle (EV) morphology, flow cytometry measured platelet activation, reactive oxygen species (ROS), and exocrine protein expression, while ELISA quantified secretory proteins. Tumor control and platelet function were studied in tumor-bearing mice. We identified that hematological profiles of NSCLC patients frequently manifest a hypercoagulable state relative to healthy controls and lung cancer cells could instigate platelet activation, yet resveratrol could attenuate this phenomenon induced by lung cancer. Resveratrol stimulates lung cancer cells to release HMGB1-enriched EVs, promoting platelet ferroptosis and inhibiting platelet activation through increased ROS, lipid peroxidation, and disrupted cystine transporters. In vivo studies confirm that resveratrol inhibits lung cancer cell growth and suppresses tumor-induced platelet activation in mice. Our studies revealed that resveratrol alleviated lung cancer-induced ferroptosis associated platelet activation. This suggests a potential pharmacological approach for preventing and treating both lung cancer and CAT.

Advances in Understanding How RhoB Regulates Akt Inhibition Efficacy in NSCLC.

Increasing the effectiveness and reliability of Akt inhibition in lung cancer treatment may pave the way for a more favorable use of this method in the future. Therefore, we aimed to evaluate the possible role of RhoB in the regulation of Akt inhibition in NSCLC. The study was conducted using the NSCLC cell line A549. Small interfering RNA (siRNA)-mediated RhoB knockdown was performed and combined with perifosine (Akt inhibitor) treatment. Cell proliferation was detected by xCELLigence® RTCA. RhoB, pAkt, and Bcl2l11 expressions were analyzed by ELISA. Apoptosis rates were determined by flow cytometry. We knocked down RhoB in A549 cells using siRNA. According to the results of the 72-hour experiment, RhoB upregulation was observed to reduce the antiproliferative ac-tivity of the Akt inhibitor. The pAkt level was significantly lower in the group where the Akt inhibitor was applied to RhoB-silenced cells via siRNA compared to other treatment groups. The percentage of apoptosis in the group where the Akt inhibitor was applied to RhoB-silenced cells was found to be significantly higher than in the RhoB-suppressed group. Both proliferation and apoptosis tests determined that the RhoB molecule is a negative regulator of the anti-tumor activity of Akt inhibition in non-small cell lung cancer. This study suggests that RhoB expression may play a critical role in the regulation of Akt inhibition in NSCLC, potentially opening new avenues for treatment strategies.

The histone lactylation of AIM2 influences the suppression of ferroptosis by ACSL4 through STAT5B and promotes the progression of lung cancer.

Lung cancer progression is characterized by intricate epigenetic changes that impact critical metabolic processes and cell death pathways. In this study, we investigate the role of histone lactylation at the AIM2 locus and its downstream effects on ferroptosis regulation and lung cancer progression. We utilized a combination of biochemical assays, including chromatin immunoprecipitation (ChIP), quantitative real-time PCR (qRT-PCR), and western blotting to assess histone lactylation levels and gene expression. To evaluate the functional consequences, we employed gain- and loss-of-function approaches using shikonin treatment and siRNA knockdowns in lung cancer cell lines. Additionally, we assessed the impact of these interventions on ferroptosis markers and lung cancer cell viability. Our results reveal that increased histone lactylation at the AIM2 locus correlates with enhanced transcriptional activity of AIM2, leading to reduced ferroptosis through modulation of ACSL4 and STAT5B. Furthermore, we demonstrate that shikonin, a natural naphthoquinone derivative, effectively downregulates PKM2 and AIM2 expression, thereby inhibiting lung cancer progression by counteracting the effects of histone lactylation on AIM2 expression. These findings highlight the importance of histone lactylation in regulating AIM2 expression and ferroptosis in lung cancer cells. They also suggest that targeting PKM2 and AIM2, particularly through the use of shikonin, could be a promising strategy for developing novel therapies against lung cancer.

Proteomic analysis reveals anticancer mechanisms of Bhallataka taila in inhibiting lung cancer progression and metastasis.

Lung cancer remains the leading cause of cancer-related deaths worldwide due to its poor prognosis. Despite significant advancements in the understanding of cancer development, improvements in diagnostic methods, and multimodal therapeutic regimens, the prognosis of lung cancer has still not improved. Therefore, it is reasonable to look for newer and alternative medicines for treatment. Bhallataka nut extract, derived from the seeds of Semecarpus anacardium, is known for its anti-inflammatory and antioxidant properties, suggesting potential as a treatment for cancer. In this study, we investigated the molecular networks associated with the Bhallataka taila-mediated inhibition of lung adenocarcinoma. Treating lung cancer cell lines with Bhallataka taila resulted in decreased colony formation, proliferation, and migration, and increased apoptosis. Using a tandem mass tag (TMT)-based temporal quantitative proteomic analysis, we identified 173 overexpressed and 249 downregulated proteins among a total of 2879 proteins. Significantly altered proteins are associated with lung cancer progression, metastasis, invasion, migration, and epithelial-mesenchymal transition (EMT). The analysis of these altered proteins revealed molecular networks underlying the anticancer mechanisms of Bhallataka taila. Validation of these proteins and pathways affected by Bhallataka taila confirmed its utility in cancer treatment.

Functional proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer

Functional proteomics-based investigation of the cellular response to farnesyltransferase inhibition in lung cancer

The effectiveness of sanggenon c in alleviating SLC7A11-induced ferroptosis in lung cancer was evaluated using in vivo, in vitro, and computational approaches.

Sanggenon c, a component in Morus alba L, has been proved to possess various biological activities. The aim of this study is to investigate whether sanggenon c can target SLC7A11 and inhibit lung cancer by regulating the ferroptosis mechanism. The levels of antioxidant factor, Fe 2+, and SLC7A11 were measured in the lungs of cancerous mice and human A 549 lung cancer cells. The computer-aided techniques were employed to validate the molecular docking and molecular dynamics simulations of sanggenon c and SLC7A11. The sanggenon c significantly inhibits lung cancer cell metastasis in vivo and A 549 cell proliferation in vitro by targeting the over-expression of SLC7A11, which inhibits GPX 4 and induces the release of ROS and MDA, effectively triggering ferroptosis. The interaction between sanggenon c and SLC7A11 exhibits a strong binding affinity, leading to the significant inhibition of the key protein SLC7A11. This restriction of system xc- transport induces ferroptosis in lung cancer. It epitomizes a groundbreaking inhibitor specifically designed to target SLC7A11.

Rabeprazole inhibits lung cancer progression by triggering NLRP3/CASP-1/caspase-dependent pyroptosis.

Gastric acid-related diseases could be treated using proton pump inhibitors (PPIs), which have been found to have anti-tumor ability. Rabeprazole is a type of PPI whose effect and mechanism in lung cancer remained to be clarified. Lung cancer cells and lung cancer mice were treated with different concentrations of Rabeprazole and then cell proliferation was detected by CCK-8 and colony formation assays. Pyroptosis was assessed by morphological observation and Lactate dehydrogenase (LDH) release assays. Western blot, immunofluorescence and immunohistochemistry were adopted to detect the expressions of GSDMD and NLRP3. Reactive oxygen species (ROS) level, lysosomal damage and autophagic flux were measured by flow cytometry. Rabeprazole suppressed lung cancer cell proliferation and lung tumor growth in mice in a concentration-dependent manner. Lung cancer cells treated with Rabeprazole showed typical pyroptosis morphology and significantly increased LDH release. Rabeprazole upregulated the expression of GSDMD, NLRP3, and cleaved-Caspase 1, but such an effect was partially blocked by Z-LLSD-FMK. In lung cancer cells treated with Rabeprazole and lung cancer mice injected with Rabeprazole, the expressions of GSDMD, NLRP3 and caspase-1 were promoted, ROS-stained cells were increased significantly, lysosomal damage was aggravated, and autophagic flux was noticeably reduced. Rabeprazole activated NLRP3/caspase 1/GSDMD cascade by promoting ROS accumulation and lysosomal destruction, thereby inducing pyroptosis to fulfill its anti-tumor effect on lung cancer.

Carbamazepine Inhibits Lung Cancer Metastasis by Suppressing Chemokine Receptor 4 Expression.

Lung cancer is one of the leading causes of cancer-related deaths worldwide, with treatment failure resulting from metastasis. C-X-C chemokine receptor type 4 (CXCR4) plays a crucial role in tumor cell migration and metastasis. Recent studies have suggested that the commonly used antiepileptic drug, carbamazepine (CBZ), may impede tumor metastasis; however, its specific mechanism remains unclear. In this study, we evaluated the effects of CBZ on the migration and invasion of lung cancer cells through in vitro cell cultures and in vivo animal models. The regulatory effect of CBZ on CXCR4 expression was analyzed using western blot and reverse transcription-quantitative polymerase chain reaction techniques. To further validate whether CBZ's anti-metastatic effect is mediated through CXCR4, we used the CXCR4 agonist NUCC-390 and overexpression of the CXCR4 gene in lung cancer cell lines. The results demonstrated that CBZ significantly inhibited the migration and invasion of lung cancer cells (*p < 0.001). In animal experiments, CBZ treatment significantly reduced the extent of metastasis in the lungs (*p < 0.01). Moreover, CBZ downregulated the expression of CXCR4 (*p < 0.001). When NUCC-390 was used or CXCR4 was overexpressed, the anticancer effect of CBZ was reversed, indicating the anti-metastatic effect of CBZ is closely associated with its inhibition of CXCR4 expression. This study reveals, for the first time, a novel mechanism by which CBZ inhibits lung cancer metastasis through the suppression of CXCR4 expression. These findings offer a new avenue for the treatment of lung cancer using CBZ as a potential agent against lung cancer metastasis. Further research is warranted to explore the clinical potential of CBZ and to offer more treatment options for lung cancer patients.

Stimuli-responsive benzothiazole-phenothiazine derivatives: mechanochromism, AIE, acid sensing, and anticancer efficacy in benzo[a]pyrene-induced cancer models.

Mechanofluorochromic (MFC) materials are emerging as a versatile candidate for optoelectronic and biomedical applications. In the present work, we designed and synthesized four MFC materials, namely BT-PTZ-1, BT-PTZ-2, BT-PTZO-1, and BT-PTZO-2, using Suzuki cross-coupling reaction. These materials possess benzothiazole (BT) as an acceptor moiety and different donors, including phenothiazine (PTZ) and triphenylamine (TPA), with variations in their spacer units. The photophysical properties of these derivatives have been explored, revealing solvatochromism, aggregation-induced emission (AIE), acid sensing, and mechanochromic behaviour. Single crystal X-ray analysis of BT-PTZO-2 provides crucial structural insights, revealing the twisted conformation of the TPA donor and the bent structure of the PTZ oxide spacer. The biological studies of these BT derivatives reveal the therapeutic potential against benzo[a]pyrene (B[a]P)-induced carcinogenesis in A549 (lung) and HEK293 (kidney) cells. Treatment with BT-PTZ-2 reflects anti-cancerous properties, with significant up-regulation of p53 and down-regulation of β-catenin and pNF-κB. Additionally, downregulation of mitochondrial fission protein (DRP1) and oxidative stress through DCFDA staining in lung cells are observed with BT-PTZ-2 treatment. These findings strongly suggest that BT-PTZ-2 can inhibit lung cancer cell proliferation and survival, suggesting it to be a promising anti-cancer agent. This comprehensive study of these MFC materials provides insights into their design, synthesis, and properties, in addition to their potential applications in various optoelectronic and biomedical fields.

Discovery of novel fluorine-containing parthenolide analogues as potential antitumor agents.

Incorporating fluorine-containing groups into the chemical skeleton is expected to enhance bioactivity and bioavailability. Directly introducing fluorine groups into the parthenolide skeleton remains challenging and limited. In this research, a series of novel fluorine-containing parthenolide derivatives were synthesized through late-stage diversification strategy. And the most promising derivate 1 exhibited good antiproliferative activity against NCI-H820 (IC50: 2.66μM), Huh-7 (IC50: 2.36μM), and PANC-1(IC50: 2.16μM). The preliminary mechanism study indicated compound 1strongly inhibited the colony formation number of NCI-H820, Huh-7 and PANC-1cells and inhibited lung cancer metastasis with a dose-dependent manner through inhibiting STAT3 signaling pathway. Compound 16, a prodrug of compound 1, showed a significant improvement in aqueous solubility and oral bioavailability compared with parthenolide. Moreover, compound 16 significantly suppressed tumor growth in lung patient-derived tumor xenograft model without obvious toxicity. Based on the above results, we propose that compound 16 may be a promising lead compound for treatment of lung cancer.

Progress of Ginsenosides on Immunomodulation and Inhibition of Lung Cancer

Ginseng is characterized by low toxicity, multi-targeting and enhancement of body immunity in its anti-cancer effects. Ginsenosides are natural effective anti-cancer components, mainly consisting of diol-type, triol-type, and oleanolic acid-type ginsenosides. Ginsenosides are bio absorbed by intestinal flora through "Rb1-Gibberellin XVII-F2-CK-PPD", "Rb2-Rd-F2-CK-PPD", "Rg3-Rh2-PPD" and other pathways. It can be converted into saponins ck, Rh1, Rh2, Rc, PPD and other active ingredients. Metabolites of ginsenosides are used in the treatment of many types of cancers and have been shown to be effective. They function by modulating various immune cells in the body, for example, ginsenoside Rh2 significantly increases T-lymphocyte activity and significantly induces differentiation of M2 macrophages towards the M1 phenotype. Ginsenoside Rg3 can act as a cytotoxic activator of NK cells, which inhibits the growth of tumor cells and induces apoptosis and autophagy of tumor cells, and plays an inhibitory and therapeutic role in lung cancer and a variety of tumors, with certain prospects for application development. This review introduces mechanism and function of ginsenosides and discusses application in lung cancer.

TRF-16 Inhibits Lung Cancer Progression by Hindering the N6-Methyladenosine Modification of CPT1A mRNA.

Transfer RNA-derived fragments (tRFs) are a new class of small non-coding RNAs. Recent studies suggest that tRFs participate in some pathological processes. However, the biological activities and processes of tRFs in lung cancer cells remain mainly unclear. In the present investigation, we employed tRNA-derived small RNA (tsRNA) sequencing to predict differentially expressed tsRNAs in lung cancer cells, and nine tsRNAs with significant expression alterations were validated using qPCR. Wound healing, colony formation, transwell invasion and CCK-8 assays were performed to detect the effects of tRF-16 on cell function. Western blotting evaluated the relationship between tRF-16 and the IGF2BP1 axis. Our findings demonstrated that tRF-16 expression was substantially downregulated in lung cancer cells. TRF-16 could inhibit lung cancer cells' ability to increase, migrate, invade and obtain radiation resistance. Furthermore, tRF-16 decreases the stability of CPT1A by impairing the binding of IGF2BP1 to CPT1A. As a result, the fatty acid metabolism in lung cancer cells was inhibited. Finally, tRF-16 also inhibits lung cancer cell proliferation invivo. This study shows that tRF-16 plays a crucial regulatory role in the proliferation of lung cancer cells and may represent a novel avenue for their regulation.

Exploring PDK3 inhibition in lung cancer through drug repurposing for potential therapeutic interventions

The pyruvate dehydrogenase kinase-3 (PDK3) plays an important role in the regulation of a variety of cancers, including lung, by inhibiting the pyruvate dehydrogenase complex (PDC), shifting energy production towards glycolysis necessary for cancer metabolism. In this study, we aimed to identify potential PDK3 inhibitors using a computer-based drug design approach. Virtual screening of the FDA-approved library of 3839 compounds was carried out, from which Bagrosin and Dehydrocholic acid appeared best due to their strong binding affinity, specific interactions, and potential biological characteristics, and thus were selected for further investigations. Both compounds show strong interactions with functionally important residues of the PDK3 with a binding affinity of − 10.6 and − 10.5 kcal/mol for Bagrosin and Dehydrocholic acid, respectively. MD simulation studies for 100 ns suggest the formation of stable complexes, which is evident from RMSD, RMSF, Rg, and SASA parameters. The PCA and FEL analysis suggested admirable global energy minima for the bagrosin-PDK3 and dehydrocholic acid-PDK3 complexes. Finally, we identified FDA-approved drugs, Bagrosin and Dehydrocholic acid, that offer valuable resources and potential therapeutic molecules for targeting lung cancer. Further clinical investigations are required to validate the clinical utility of selected molecules.

PRKDC regulates cGAMP to enhance immune response in lung cancer treatment.

Despite its involvement in nucleotide metabolism, tumor immune landscape, and immunotherapy response, the role of 2'-3'-cyclic guanosine monophosphate-adenosine monophosphate (2',3'-cGAMP) in lung adenocarcinoma (LUAD) remails unelucidated. This study aimed to investigate the antitumor effects of 2',3'-cGAMP in LUAD. Herein, patients with LUAD were screened for prognostic biomarkers, which were then assessed for sensitivity to immunotherapy and chemotherapy utilizing the "TIDE" algorithm and CellMiner database. The results were validated using a mouse xenograft model. Additionally, macrophages and lung cancer cells were co-cultured, and macrophage polarization and apoptosis levels in the lung cancer cells were detected through flow cytometry. Protein levels were analyzed through western blotting and immunofluorescence. Finally, drug-encapsulated nanoparticles were designed to systematically examine the antitumor efficacy of the treatment against LUAD. Notably, 2',3'-cGAMP-mediated protein kinase, DNA-activated, catalytic subunit (PRKDC) inhibition induced macrophage polarization toward the M1 phenotype, thereby triggering apoptosis in LUAD cells. Furthermore, in vivo experiments showed that M1 macrophage infiltration enhancement and apoptosis induction in lung cancer cells were achieved by suppressing PRKDC expression via 2',3'-cGAMP, which inhibited lung cancer growth. The machine-learning approaches revealed SB505124 to be an effective antitumor agent in LUAD cells with high PRKDC levels owing to its ability to promote 2',3'-cGAMP-mediated apoptosis. Encapsulation of 2',3'-cGAMP, and SB505124 within a nano-delivery system markedly reduced tumor volumes in murine lung cancer tissues compared with that by individual agents. The findings of this study reveal that PRKDC can predict poor survival of patients with LUAD. Additionally, SB505124 enhances the efficacy of 2',3'-cGAMP-based immunotherapy in patients exhibiting a high PRKDC expression.

Maimendong decoction inhibits lung cancer metastasis by increasing the proportion and killing activity of NK cells

Ethnopharmacological relevanceIn China, Maimendong Decoction (MMDD) is a classic Chinese medicine prescription for treating lung diseases, such as cough, upper respiratory tract infection, bronchitis, asthma, pulmonary fibrosis and so on. However, the mechanism by which MMDD inhibits lung cancer metastasis remains unclear. Aim of the studyThis study seeks to examine the effect of MMDD on suppressing lung cancer metastasis and to uncover its mechanism through the regulation of tumor immunity. Materials and methodsThe impact of MMDD on lung cancer cell growth and metastasis was assessed via cell apoptosis, proliferation, and migration assays, alongside lung metastasis models in mice. Hematoxylin-eosin (H&E) staining, immunohistochemistry, and immunofluorescence were used to examine the tissue morphology of metastatic tumors, Ki-67 protein expression, and NK cell infiltration. The potential anti-lung cancer mechanism of MMDD was explored through network pharmacology. Immune cell levels and NK cell function in mouse peripheral blood were analyzed using flow cytometry. Additionally, co-culture and lactate dehydrogenase (LDH) assays were performed to assess NK cell cytotoxicity. ResultsMMDD significantly reduced the number of metastatic tumors and the neoplastic burden in the lungs of mice. While MMDD did not affect the proliferation, apoptosis, or migration of lung cancer cells at 1 mg/ml concentration in vitro, it substantially increased NK cell proportion in peripheral blood and metastatic tumor tissues. Moreover, MMDD significantly boosted NK cell cytotoxicity and enhanced their killing effect on lung cancer cells. Importantly, depletion of NK cells abolished the survival-prolonging effect of MMDD in mice. ConclusionThis study demonstrates that MMDD restrains lung cancer cell metastasis primarily by increasing NK cell levels and enhancing their cytotoxic activity. These results offer experimental support for the use of MMDD in treating lung cancer metastasis.

Enhancing lung cancer growth inhibition with calcium ions: Role of mid- and high-frequency electric field pulses

Calcium electroporation (CaEP) involves the combination of calcium ions with electroporation, which is induced by pulsed electric fields (PEFs). This study explores the application of high-frequency unipolar nanosecond pulsed electric fields (nsPEFs: 8–14 kV/cm, 200 ns, 10 kHz, 100 kHz, 1 MHz repetition frequency pulse bursts, n = 100) and their potential in inhibiting lung cancer cell growth. As a reference, standard microsecond range parametric protocols were used (100 µs x 8 pulses). Methods included cell permeability quantification through Yo-Pro-1 uptake, cell viability assays, immunofluorescence studies for apoptosis and EMT markers, analysis of cell death types depending on repetition frequency pulse bursts. We determined the susceptibility of human lung cancer to electric pulses, characterized the efficacy of CaEP, and investigated cell death types depending on repetition frequency pulse bursts. We have shown that adding calcium ions to the applied nsPEF protocol increases cytotoxicity. Additionally, the use of these electroporation parameters can modulate key cellular processes, such as the epithelial-mesenchymal transition and apoptosis, as indicated by changes in the expression of markers such as E-cadherin, N-cadherin, BCL-2, and p53. Changes in cell morphology over time were observed using holotomographic microscopy. The study provides insights into the modulation of key cellular processes, indicating that nsPEF technology could improve the outcomes of conventional cancer treatments through enhanced efficacy and potentially mitigating drug resistance mechanisms. The promising results advocate for further research to optimize nsPEF protocols for clinical application, highlighting the potential of electrical fields in advancing cancer therapy.

Cremastrae Pseudobulbus Pleiones Pseudobulbus (CPPP) Against Non-Small-Cell Lung Cancer: Elucidating Effective Ingredients and Mechanism of Action.

Cremastrae Pseudobulbus Pleiones Pseudobulbus (CPPP) is derived from the dried pseudobulb of the orchid family plants Cremastra appendiculata (D.Don) Makino, Pleione bulbocodioides (Franch.) Rolfe, or Pleione yunnanensis Rolfe, and has the properties of clearing heat, detoxification, resolving phlegm, and dispersing nodules. It is frequently used for the treatment of various malignant tumors in clinical practice, especially lung cancer. CPPP is divided into two commercial specifications in the market, Maocigu (MCG) and Bingqiuzi (BQZ). However, owing to a lack of appropriate research strategies, the active ingredients and molecular mechanisms involved have not yet been clarified. This study intended to discover the combination of effective anti-lung-cancer ingredients in CPPP and explore their potential mechanisms of action. In this study, UHPLC-MS fingerprints of MCG and BQZ were established separately. Inhibitory effects on the proliferative viability and migratory ability of A459 and H1299 cells were evaluated as pharmacodynamic indicators. GRA and BCA were used to determine spectrum-effect relationships. Next, the identification and analysis of components of drug-containing serum were performed using UHPLC-Q-Exactive Orbitrap MS. Then, the results of the two analyses were combined to jointly screen out the anti-lung-cancer candidate active monomers of CPPP, and their in vitro activities were verified. Afterward, all effective ingredient combinations of MCG (MCGC) and BQZ (BQZC) were prepared according to their contents in the original medicinal materials. Their anti-lung-cancer activities in vitro and in vivo were compared and verified. Finally, we used the human lung cancer cell line A549 and the Lewis tumor xenograft model to investigate how BQZC would influence autophagy and apoptosis processes and the mechanisms involved. Overall, 11 predominant anti-lung-cancer active ingredients from CPPP were screened. Next, MCGC and BQZC were prepared according to their contents in the original medicinal materials, respectively, and their anti-tumor effects were equivalent to those of the original materials in vitro and in vivo. We found that BQZC could inhibit lung cancer cell growth and induce protective autophagy and apoptosis in lung cancer cells by activating the AMPK-mTOR-ULK1/BMF signaling pathway. These results provide important evidence for the clinical application and deep development of CPPP against tumors.

RIPK2 and lysosomal pathway: Unveiling a new mechanism for lung cancer metastasis

BackgroundThis study aims to explore the role of RIPK2 in lung cancer metastasis and its potential mechanisms. MethodsThe expression levels of RIPK2 in lung cancer patients and cell lines were detected by immunohistochemistry, qRT-PCR, and Western blot. RIPK2 expression was knocked down using siRNA technology, and its effects on the proliferation, migration, and invasion capabilities of lung cancer cells were assessed through CCK-8, EdU, colony formation, and Transwell assays. Furthermore, by overexpressing RIPK2 and LAMP2, the regulatory effect of RIPK2 on the lysosomal pathway and its mechanism of action in lung cancer metastasis were investigated. ResultsThe results showed that the expression of RIPK2 was significantly increased in lung cancer patients and cell lines. Knockdown of RIPK2 significantly inhibited the migration, invasion, and proliferation capabilities of lung cancer cells, while overexpression of RIPK2 promoted these malignant behaviors. Further studies found that RIPK2 promoted lung cancer metastasis by inhibiting LAMP2 expression, thereby suppressing the lysosomal pathway and altering the tumor microenvironment. Additionally, overexpression of LAMP2 could reverse the promotive effects of RIPK2 overexpression on the malignant behaviors of lung cancer cells. ConclusionThis study reveals for the first time that RIPK2 promotes lung cancer metastasis by inhibiting LAMP2 expression, thereby suppressing the lysosomal pathway and altering the tumor microenvironment. In the future, targeted therapy against RIPK2 and LAMP2 may become an effective means to inhibit lung cancer metastasis.