Xueni Sun

Ponicidin, a bioactive diterpenoid derived from Rabdosia rubescens, has been shown to exhibit antitumor activity across a range of cancer types. Despite its potential therapeutic applications, the precise effects and underlying molecular mechanisms of ponicidin in the context of lung cancer remain insufficiently characterized. This study aims to investigate the antitumor effects of ponicidin in lung cancer, focusing on its impact on cell growth and cellular oxidative stress. Our findings demonstrate that ponicidin significantly inhibits the viability of lung cancer cells while exhibiting minimal cytotoxicity to normal lung cells. Notably, ponicidin induces cell death in lung cancer cells via the induction of oxidative stress, a process likely mediated by the depletion of sulfhydryl antioxidants and the downregulation of thioredoxin reductase (TrxR), both of which play critical roles in maintaining cellular redox homeostasis. Moreover, ponicidin was found to concurrently activate endoplasmic reticulum stress, induce mitochondrial dysfunction, and promote DNA damage, further contributing to its antitumor effects. In vivo, the efficacy of ponicidin was confirmed in tumor-bearing mouse models, where ponicidin treatment led to a significant reduction in tumor growth without significant toxicity or adverse effects on the animals. These findings suggest that ponicidin holds significant promise as a safe and effective therapeutic agent for lung cancer, warranting further investigation into its clinical applicability.

Background: This study investigated the therapeutic effects and underlying mechanisms of abietic acid, an abietane diterpene extracted from Pimenta racemosa var. grissea, against lung cancer. Methods: Initially, cell viability, colony formation, flow cytometry, and mitochondrial membrane potential detection were conducted to determine the impact of abietic acid on lung cancer cells. Subsequently, the antitumor mechanisms of abietic acid were predicted using network pharmacology and validated via immunofluorescence, reactive oxygen species (ROS) detection, molecular docking, gene knockdown techniques and Western blotting. Finally, an in vivo xenograft model assessed its tumor-suppressive potential, with Hematoxylin–Eosin (H&E) staining, Western blotting, and immunohistochemistry performed to examine pathological changes and protein expression alterations. Results: The proliferation of lung cancer cells was significantly inhibited by abietic acid. Additionally, abietic acid induced apoptosis and reduced mitochondrial membrane potential. Network pharmacology and Gene Ontology (GO) enrichment analysis revealed that the DNA damage response was a key biological process affected by abietic acid. Further results demonstrated that abietic acid induces DNA damage in lung cancer cells through targeting DNA topoisomerase II alpha (TOP2A). In vivo studies confirmed the antitumor efficacy of abietic acid and its low systemic toxicity. Conclusions: Abietic acid demonstrated significant antitumor effects in lung cancer cells by downregulating TOP2A, which induced DNA damage and apoptosis, revealing its clinical potential.

Lung cancer continues to be a significant clinical challenge, highlighting the urgent need for effective therapeutic strategies to improve patient outcomes. Poricoic acid A (PAA), an active compound derived from the traditional Chinese medicinal mushroom Poria cocos (Fuling), has gained attention for its potential antitumor effects. Although prior studies have suggested its efficacy in vitro, the therapeutic potential, mechanism of action, and safety of PAA in inhibiting cancer growth have yet to be thoroughly investigated. The aim of this study was to explore the therapeutic potential of PAA against lung cancer through comprehensive in vitro and in vivo experiments. In vitro, H460 and H1299 lung cancer cells were treated with PAA to evaluate its impact on cell growth, apoptosis, and the cell cycle using CCK‐8 assay, colony formation assay, and flow cytometry analyses. In vivo, mouse models were used to assess both the efficacy of PAA in inhibiting tumor growth and its safety across primary organs. PAA significantly inhibited the growth of lung cancer cells, induced apoptosis, and caused cell cycle arrest in the G₂/M phase. Mechanistic investigations revealed that PAA directly targeted MEK1/2, resulting in the downregulation of the MEK/ERK signaling pathway and subsequent suppression of cell growth and proliferation. In mouse models, PAA exhibited low toxicity and minimal adverse effects on primary organs. PAA holds promise as a potential therapeutic agent for lung cancer, providing a solid foundation for future clinical investigation.

Background: Pancreatic cancer is highly aggressive with limited treatment options. PLA2G16 has been implicated in cancer progression, but its role in prognosis and gemcitabine sensitivity in pancreatic cancer remains poorly understood. Methods: Using TCGA data, the study assessed the correlation between PLA2G16 expression and patient survival. The expression of PLA2G16 in gemcitabine-resistant versus sensitive pancreatic cancer cells was also compared. siRNA-mediated knockdown of PLA2G16 was performed in drug-resistant PANC-1 cells to evaluate its impact on gemcitabine sensitivity. The relationship between PLA2G16 expression, immune infiltration, and molecular pathways in pancreatic cancer was explored using CIBERSORT and DAVID tools. Results: PLA2G16 was significantly overexpressed in pancreatic cancer tissues and associated with poorer patient survival. In PANC-1 cells, increased PLA2G16 expression correlated with gemcitabine resistance, and its knockdown improved drug sensitivity. PLA2G16 expression was linked to specific immune infiltration patterns and cancer-related molecular pathways. Conclusions: Elevated PLA2G16 expression is associated with poor survival and gemcitabine resistance in pancreatic cancer, making it a potential prognostic marker and therapeutic target.

Lung cancer remains one of the most widespread and deadliest malignant tumors globally, with a particularly high mortality rate among all cancers. Recently, immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a crucial treatment strategy for lung cancer patients, following surgical intervention, radiotherapy, chemotherapy, and targeted drug therapies. However, the therapeutic limitations are caused owing to their low response rate and undesirable side effects such as immune‐related pneumonitis. Therefore, developing new strategies to improve the efficacy of ICIs while minimizing immune‐related adverse events will be crucial for cancer immunotherapy. The tumor immune microenvironment plays a significant role in the success of lung cancer immunotherapy, and the immunosuppressive characteristics of the immune microenvironment are one of the major obstacles to the poor immunotherapeutic effect. Phytochemicals, naturally occurring compounds in plants, have shown promise in enhancing cancer immunotherapy by remodeling the immunosuppressive microenvironment, offering the potential to increase the efficacy of ICIs. Therefore, this review summarizes the associated mechanisms of phytochemicals remodeling the immunosuppressive microenvironment in lung cancer. Additionally, the review will focus on the synergistic effects of combining phytochemicals with ICIs, aiming to improve anticancer efficacy and reduce side effects, which may hopefully offer novel strategies to overcome current limitations in immunotherapy.

Objective: Erianin has potential anticancer activities, especially against lung cancer. The specific mechanisms underlying the anti-cancer effects, including the molecular targets and signaling pathways in lung cancer, remain poorly understood and necessitate further investigation. Methods: Lung cancer cell viability was evaluated using the CCK-8 assay. Flow cytometry was used to examine the effects of erianin on apoptosis and cell cycle progression. mRNA sequencing and metabolomics analysis were utilized to explore erianin-induced biological changes. Potential targets were identified and validated through molecular docking and Western blot analysis. The roles of mammalian target of rapamycin (mTOR) and carbamoyl-phosphate synthetase/aspartate transcarbamylase/dihydroorotase (CAD) in erianin-induced growth inhibition were studied using gene overexpression/knockdown techniques with uridine and aspartate supplementation confirming pyrimidine metabolism involvement. Additionally, lung cancer-bearing nude mouse models were established to evaluate the anti-lung cancer effects of erianin in vivo. Results: Erianin significantly inhibits the proliferation of lung cancer cells, induces apoptosis, and causes G₂/M phase cell cycle arrest. Integrative analysis of mRNA sequencing and metabolomics data demonstrated that erianin disrupts pyrimidine metabolism in lung cancer cells. Notably, uridine supplementation mitigated the inhibitory effects of erianin, establishing a connection between pyrimidine metabolism and anticancer activity. Network pharmacology analyses identified mTOR as a key target of erianin. Erianin inhibited mTOR phosphorylation, thereby blocking downstream effectors (S6K and CAD), which are essential regulators of pyrimidine metabolism. Conclusions: Erianin is a promising therapeutic candidate for lung cancer. Erianin likely inhibits lung cancer cell growth by disrupting pyrimidine metabolism by suppressing mTOR activation.

The disruption of zinc (Zn) homeostasis has been implicated in cancer development and progression through various signaling pathways. Maintaining intracellular zinc balance is crucial in the context of cancer. Human cells rely on two families of transmembrane transporters, SLC30A/ZNT and SLC39A/ZIP, to coordinate zinc homeostasis. While some ZNTs and ZIPs have been linked to cancer progression, limited information is available regarding the expression patterns of zinc homeostasis-related genes and their potential roles in predicting prognosis and developing therapeutic strategies for specific cancers. In this study, a systematic analysis was conducted to examine the expression of all genes from the SLC30A and SLC39A families at both mRNA and protein levels across different cancers. As a result, three SLC39A genes (SLC39A1, SLC39A4, and SLC39A8) were found to be significantly dysregulated in specific cancers, including cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), liver hepatocellular carcinoma (LIHC), pancreatic adenocarcinoma (PAAD), and kidney renal papillary cell carcinoma (KIRP). Moreover, the dysregulation of these genes was tightly associated with the prognosis of patients with those cancers. Furthermore, we found that the gene SLC39A8 exhibited the lowest mutation frequency in KIRP, whereas mutations in SLC39A4 were found to significantly impact overall survival (OS), disease-free (DF), and progress-free survival (PFS) in cancer patients, particularly in those with PAAD. Additionally, immune infiltration analysis revealed that SLC39A1, SLC39A4, and SLC39A8 may function as immune regulators in cancers. This provides new insights into understanding the complex relationship between zinc homeostasis and cancer progression.

Background: Despite the critical progress of non-small cell lung cancer (NSCLC) therapeutic approaches, the clinical outcomes remain considerably poor. The requirement of developing novel therapeutic interventions is still urgent. In this study, we showed for the first time that diosbulbin C, a natural diterpene lactone component extracted from traditional Chinese medicine Dioscorea bulbifera L., possesses high anticancer activity in NSCLC. Methods: A549 and NCI-H1299 cells were used. The inhibitory effects of the diosbulbin C on NSCLC cell proliferation were evaluated using cytotoxicity, clone formation, EdU assay, and flow cytometry. Network pharmacology methods were used to explore the targets through which the diosbulbin C inhibited NSCLC cell proliferation. Molecular docking, qRT-PCR, and western blotting were used to validate the molecular targets and regulated molecules of diosbulbin C in NSCLC. Results: Diosbulbin C treatment in NSCLC cells results in a remarkable reduction in cell proliferation and induces significant G0/G1 phase cell cycle arrest. AKT1, DHFR, and TYMS were identified as the potential targets of diosbulbin C. Diosbulbin C may inhibit NSCLC cell proliferation by downregulating the expression/activation of AKT, DHFR, and TYMS. In addition, diosbulbin C was predicted to exhibit high drug-likeness properties with good water solubility and intestinal absorption, highlighting its potential value in the discovery and development of anti-lung cancer drugs. Conclusions: Diosbulbin C induces cell cycle arrest and inhibits the proliferation of NSCLC cells, possibly by downregulating the expression/activation of AKT, DHFR, and TYMS.

Erianin is a major bisbenzyl compound extracted from Dendrobium chrysotoxum Lindl., an important traditional Chinese herb. In recent years, a growing body of evidence has proved the potential therapeutic effects of erianin on various cancers, including hepatoma, melanoma, non-small-cell lung carcinoma, myelogenous leukemia, breast cancer, and osteosarcoma. Especially, the pharmacological activities of erianin, such as antioxidant and anticancer activity, have been frequently demonstrated by plenty of studies. In this study, we firstly conducted a systematic review on reported anticancer activity of erianin. All updated valuable information regarding the underlying action mechanisms of erianin in specific cancer was recorded and summarized in this paper. Most importantly, based on the molecular structure of erianin, its potential molecular targets were analyzed and predicted by means of the SwissTargetPrediction online server (http://www.swisstargetprediction.ch). In the meantime, the potential therapeutic targets of 10 types of cancers in which erianin has been proved to have anticancer effects were also predicted via the Online Mendelian Inheritance in Man (OMIM) database (http://www.ncbi.nlm.nih.gov/omim). The overlapping targets may serve as valuable target candidates through which erianin exerts its anticancer activity. The clinical value of those targets was subsequently evaluated by analyzing their prognostic role in specific cancer using Kaplan-Meier plotter (http://Kmplot.com/analysis/) and Gene Expression Profiling Interactive Analysis (GEPIA) (http://gepia.cancer-pku.cn/). To better assess and verify the binding ability of erianin with its potential targets, molecular flexible docking was performed using Discovery Studio (DS). The valuable targets obtained from the above analysis and verification were further mapped to the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway using the Database for Annotation, Visualization and Integrated Discovery (DAVID) (http://david.abcc.ncifcrf.gov/) to explore the possible signaling pathways disturbed/regulated by erianin. Furthermore, the in silico prediction of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties of erianin was also performed and provided in this paper. Overall, in this study, we aimed at 1) collecting all experiment-based important information regarding the anticancer effect and pharmacological mechanism of erianin, 2) providing the predicted therapeutic targets and signaling pathways that erianin might act on in cancers, and 3) especially providing in silico ADMET properties of erianin.