Treatment Of Non-small Cell Lung Cancer Research Articles

Anthocyanins in Non-Small Cell Lung Cancer (NSCLC) Treatment and Prevention

An ever-growing volume of data supports the important role of dietary interventions in cancer prevention and the beneficial effects of plant secondary metabolites in solid tumor therapeutics [...]

Weekly Afatinib in the Treatment of Advanced Non-small Cell Lung Cancer with Egfr-G719c Mutation Followed by Lobectomy: A Case Report

Introduction: Lung cancer stands as the leading cause of cancer-related deaths worldwide. Over the past three decades, the advent of tyrosine kinase inhibitors (TKIs) has marked a significant turning point in the treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations. Notably, high response rates have been notably observed in cases with exon 19 deletions (Del19) and Exon 21 substitution L858R mutations. Conversely, the G719X mutation on exon 18 is less prevalent, with variable sensitivity across different generations of TKIs. Afatinib, a second-generation inhibitor, gained FDA approval for the initial treatment of EGFR-mutant metastatic NSCLC in 2013, though its role remains incompletely understood within a multidisciplinary treatment framework, particularly in combination with surgery. However, the standard daily dose of 40mg Afatinib has demonstrated poor tolerability, often resulting in adverse events such as diarrhea and skin toxicity, leading to treatment discontinuation. A recent strategy involving a weekly dose of 280mg Afatinib has shown promising outcomes and a reduced risk of adverse events. Case Presentation: This case report highlights a 50 - year-old female diagnosed with stage IVa right lung adenocarcinoma metastasizing to the left lung (cT3N0M1a), revealing the rare EGFR-G719C (exon18) mutation. Following this diagnosis, the patient underwent open lobectomy. Nine months post-surgery, a treatment approach involving 280mg weekly Afatinib was initiated. Subsequently, the patient was closely monitored for 16 months with no signs of recurrence. Conclusions: EGFR G719C exhibits sensitivity to Afatinib, endorsing the use of Afatinib with fewer adverse events compared to the traditional daily dosage. Our case further advocates for collaborative strategies between medical oncologists and surgeons in the management of advanced-stage NSCLC.

Current status and breakthroughs in treating advanced non-small cell lung cancer with EGFR exon 20 insertion mutations

Recently, targeted therapy and immunotherapy have emerged as effective treatment options for non-small cell lung cancer (NSCLC). This progress has been facilitated by the rapid development of diagnostic and therapeutic technologies and the continuous research and development of new drugs, leading to a new era in precision medicine for NSCLC. This is a breakthrough for patients with common mutations in the human epidermal growth factor receptor (EGFR) gene in NSCLC. Consequently, the use of targeted drugs has significantly improved survival. Nevertheless, certain rare genetic mutations are referred to as EGFR exon 20 insertion (ex20ins) mutations, which differ in structure from conventional EGFR gene mutations, namely, exon 19 deletion mutations (19-Del) and exon 21 point mutations. Owing to their distinct structural characteristics, patients harboring these EGFR ex20ins mutations are unresponsive to traditional tyrosine kinase inhibitor (TKI) therapy. This particular group of patients did not fall within the scope of their applicability. However, the activating A763_Y764insFQEA mutation elicits a more pronounced response than mutations in the near and far regions of the C-helix immediately following it and should, therefore, be treated differently. Currently, there is a lack of effective treatments for EGFR ex20ins mutations NSCLC. The efficacy of chemotherapy has been relatively favorable, whereas the effectiveness of immunotherapy remains ambiguous owing to inadequate clinical data. In addition, the efficacy of the first- and second-generation targeted drugs remains limited. However, third-generation and novel targeted drugs have proven to be effective. Although novel EGFR-TKIs are expected to treat EGFR ex20ins mutations in patients with NSCLC, they face many challenges. The main focus of this review is on emerging therapies that target NSCLC with EGFR ex20ins and highlight major ongoing clinical trials while also providing an overview of the associated challenges and research advancements in this area.

KiSS-1 Modulation by Epigenetic Agents Improves the Cisplatin Sensitivity of Lung Cancer Cells.

Epigenetic alterations my play a role in the aggressive behavior of Non-Small Cell Lung Cancer (NSCLC). Treatment with the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) has been reported to interfere with the proliferative and invasive potential of NSCLC cells. In addition, the DNA methyltransferase inhibitor azacytidine (AZA, vidaza) can modulate the levels of the metastasis suppressor KiSS-1. Thus, since cisplatin is still clinically available for NSCLC therapy, the aim of this study was to evaluate drug combinations between cisplatin and SAHA as well as AZA using cisplatin-sensitive H460 and -resistant H460/Pt NSCLC cells in relation to KiSS-1 modulation. An analysis of drug interaction according to the Combination-Index values indicated a more marked synergistic effect when the exposure to SAHA or AZA preceded cisplatin treatment with respect to a simultaneous schedule. A modulation of proteins involved in apoptosis (p53, Bax) was found in both sensitive and resistant cells, and compared to the treatment with epigenetic agents alone, the combination of cisplatin and SAHA or AZA increased apoptosis induction. The epigenetic treatments, both as single agents and in combination, increased the release of KiSS-1. Finally, the exposure of cisplatin-sensitive and -resistant cells to the kisspeptin KP10 enhanced cisplatin induced cell death. The efficacy of the combination of SAHA and cisplatin was tested in vivo after subcutaneous inoculum of parental and resistant cells in immunodeficient mice. A significant tumor volume inhibition was found when mice bearing advanced tumors were treated with the combination of SAHA and cisplatin according to the best schedule identified in cellular studies. These results, together with the available literature, support that epigenetic drugs are amenable for the combination treatment of NSCLC, including patients bearing cisplatin-resistant tumors.

The efficacy and safety of continuous intravenous infusion of rh-endostatin combined with platinum-based doublet chemotherapy for advanced non-small-cell lung cancer.

Platinum-based doublet chemotherapy is commonly used in the treatment of non-small cell lung cancer (NSCLC). A growing body of evidence indicates that incorporating antiangiogenic agents into platinum-based chemotherapy may enhance the survival outcomes for NSCLC patients. However, the optimal administration protocol for intravenous recombinant human endostatin (rh-endostatin), an antiangiogenic agent, remains uncertain at present. This study aims to investigate the efficacy and safety of 5-d continuous intravenous infusion of rh-endostatin in combination with chemotherapy for patients with advanced NSCLC. The predictive biomarkers for this treatment regimen were further probed. This prospective, single-arm multicenter study enrolled a total of 48 patients with advanced NSCLC who were histologically or cytologically confirmed but had not received any prior treatment from January 2021 to December 2022. Prior to the chemotherapy, these patients received a continuous intravenous infusion of rh-endostatin (210mg) over a period of 120h, using an infusion pump. The chemotherapy regimen included a combination of platinum with either pemetrexed or paclitaxel, given in 21-day cycles. The primary endpoint of the study was median progression-free survival (mPFS), and the secondary endpoints included median overall survival (mOS), objective response rate (ORR), disease control rate (DCR), and assessment of adverse events (AEs). The mPFS was 6.5 months (95% confidence interval (CI): 3.8-9.1m) while the mOS was 12.3 months (95% CI: 7.6-18.5m). The ORR and DCR was 52.1% and 75.0%, respectively. Leukopenia (52.1%), anemia (33.3%), and thrombocytopenia (20.8%) were the most common adverse effects and these toxicities were deemed acceptable and manageable. In addition, a correlation was noted between elevated serum carcinoembryonic antigen (CEA) levels and decreased PFS and OS. The incorporation of a 5-day continuous intravenous infusion of rh-endostatin into platinum-based doublet chemotherapy has demonstrated both safety and efficacy in the treatment of advanced NSCLC. Furthermore, the baseline serum levels of CEA may potentially function as a predictor for the efficacy of rh-endostatin when combined with chemotherapy in NSCLC patients. GOV: NCT05574998.

Treatment patterns in advanced/metastatic non-small-cell lung cancer in China: results from the CancerMPact® survey 2021.

Aim: To report the treatment patterns of advanced/metastatic non-small-cell lung cancer (NSCLC) in China from a physician survey (CancerMPact®). Materials & methods:A total of206 Chinese physicians from 27 cities in urban mainland China reported on their treatment of NSCLC in September 2021. Results: Platinum doublets received 70.5% utilization for squamous NSCLC with PD-L1 expression <1% in first-line, whereas nonsquamous NSCLC was treated with platinum doublets (35.2%) or bevacizumab with platinum doublets (35.3%). Checkpoint inhibitors were utilized in >50% of all PD-L1-positive NSCLC cases. Driver-mutated NSCLC was most frequently treated with targeted therapy or platinum-based combinations. Conclusion: NSCLC treatment in China varies by histology, PD-L1 statusand driver mutations, illustrating the complexity of decision-making for Chinese physicians as treatment markets expand.

Efficacy of neoadjuvant chemotherapy combined with surgery in patients with nonsmall cell lung cancer: A meta-analysis.

This meta-analysis sought to investigate the effect of neoadjuvant chemotherapy (NACT) combined with surgery in patients with nonsmall cell lung cancer (NSCLC). With time span from January 2010 to December 2022, PubMed, Web of Science and Embase, China National Knowledge Infrastructure, and WanFang databases were searched for randomized controlled trials on comparison between NACT combined with surgery and surgery alone in patients with NSCLC. Then a meta-analysis was performed in accordance with Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. A total of 1511 studies were retrieved and 12 were finally included. Meta-analysis results showed that compared with surgery alone, a combination of NACT and surgery was associated with higher treatment response rate (odds ratio, OR = 2.459, 95% confidence interval, CI [1.785, 3.388], P < 0.001), 1-year survival rate (OR = 2.185, 95% CI [1.608, 2.970], P < 0.001), and 3-year survival rate (OR = 2.195, 95% CI [1.568, 3.073], P < 0.001) and lower levels of intraoperative blood loss (standardized mean difference, SMD = -0.932, 95% CI [-1.588, -0.275], P = 0.005) and length of hospital stay (SMD = -0.481, 95% CI [-0.933, -0.028], P = 0.037). NACT combined with surgery is superior to surgery alone in the treatment of NSCLC and can promote postoperative recovery. Collectively, such combination is a safe and effective treatment for patients with NSCLC.

Reniformin A suppresses non-small cell lung cancer progression by inducing TLR4/NLRP3/caspase-1/GSDMD-dependent pyroptosis

Pyroptosis is an inflammatory form of programmed cell death that plays an important role in regulating tumor progression. Reniformin A (RA) is a natural compound isolated from the medicinal herb Isodon excisoides that has been applied as folk medicine in the treatment of esophageal cancer. However, whether RA has an individual function in cancer and the molecular mechanisms remain unclear. Here, we show that in non-small-cell lung cancer (NSCLC), RA inhibits tumor growth by functioning as a pyroptosis inducer to promote TLR4/NLRP3/caspase-1/GSDMD axis. Specially, RA treatment increased Toll-like receptor 4 (TLR4) protein expression level by enhancing the TLR4 stability. Based on the molecular docking, we identified that RA directly bound to TLR4 to activate the NLRP3 inflammasome and promote pyroptosis in A549 cells. Moreover, TLR4 is essential for RA-induced pyroptosis, and loss of TLR4 abolished RA-induced pyroptosis and further reduced the inhibitory effect of RA on NSCLC. In vivo experiments confirmed that RA inhibited the growth of lung tumors in mice by affecting pyroptosis in a dose-dependent manner. Furthermore, TLR4 knockdown abolished RA-induced pyroptosis and inhibited the effect of RA chemotherapy in vivo. In conclusion, we propose that RA has a significant anticancer effect in NSCLC by inducing TLR4/NLRP3/caspase-1/GSDMD-mediated pyroptosis, which may provide a potential strategy for the treatment of NSCLC.

Single-cell transcriptome analysis reveals heterogeneity of neutrophils in non-small cell lung cancer.

Lung cancer stands out as a highly perilous malignant tumor with severe implications for human health. There has been a growing interest in neutrophils as a result of their role in promoting cancer in recent years. Thus, the present study aimed to investigate the heterogeneity of neutrophils in non-small cell lung cancer (NSCLC). Single-cell RNA sequencing of tumor-associated neutrophils (TANs) and polymorphonuclear neutrophils sourced from the Gene Expression Omnibus database was analyzed. Moreover, cell-cell communication, differentiation trajectories and transcription factor analyses were performed. Neutrophils were found to be closely associated with macrophages. Four major types of TANs were identified: a transitional subcluster that migrated from blood to tumor microenvironment (TAN-0), an inflammatory subcluster (TAN-1), a subpopulation that displayed a distinctive transcriptional signature (TAN-2) and a final differentiation state that promoted tumor formation (TAN-3). Meanwhile, TAN-3 displayed a marked increase in glycolytic activity. Finally, transcription factors were analyzed to uncover distinct TAN cluster-specific regulons. The discovery of the dynamic characteristics of TANs in the present study is anticipated to contribute to yielding a better understanding of the tumor microenvironment and advancing the treatment of NSCLC.

Adverse events associated with immune checkpoint inhibitors in non-small cell lung cancer: a safety analysis of clinical trials and FDA pharmacovigilance system.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of non-small cell lung cancer (NSCLC). However, the application of ICIs can also cause treatment-related adverse events (trAEs) and immune-related adverse events (irAEs). This study was to evaluate both the irAEs and trAEs of different ICI strategies for NSCLC based on randomized clinical trials (RCTs). The study also examined real-world pharmacovigilance data from the Food and Drug Administration Adverse Event Reporting System (FAERS) regarding claimed ICI-associated AEs in clinical practice. Based on Pubmed, Embase, Medline, and the Cochrane CENTRAL, we retrieved RCTs comparing ICIs with chemotherapy drugs or with different ICI regimens for the treatment of NSCLC up to October 20, 2023. Bayesian network meta-analysis (NMA) was performed using odds ratios (ORs) with 95% credible intervals (95%CrI). Separately, a retrospective pharmacovigilance study was performed based on FAERS database, extracting ICI-associated AEs in NSCLC patients between the first quarter (Q1) of 2004 and Q4 of 2023. The proportional reports reporting odds ratio was calculated to analyze the disproportionality. The NMA included 51 RCTs that involved a total of 26,958 patients with NSCLC. Based on the lowest risk of any trAEs, cemiplimab, tislelizumab, and durvalumab were ranked as the best. Among the agents associated with the lowest risk of grades 3-5 trAEs, tislelizumab, avelumab, and nivolumab were most likely to rank highest. As far as any or grades 3-5 irAEs are concerned, atezolizumab plus bevacizumab plus chemotherapy is considered the most safety option. However, it is associated with a high risk of grades 3-5 trAEs. As a result of FAERS pharmacovigilance data analysis, 9,420 AEs cases have been identified in 7,339 NSCLC patients treated with ICIs, and ICIs were related to statistically significant positive signal with 311 preferred terms (PTs), and comprehensively investigated and identified those AEs highly associated with ICIs. In total, 152 significant signals were associated with Nivolumab, with malignant neoplasm progression, death, and hypothyroidism being the most frequent PTs. These findings revealed that ICIs differed in their safety profile. ICI treatment strategies can be improved and preventive methods can be developed for NSCLC patients based on our results.

Treatment Strategies for Non-Small-Cell Lung Cancer with Comorbid Respiratory Disease; Interstitial Pneumonia, Chronic Obstructive Pulmonary Disease, and Tuberculosis.

Non-small cell lung cancer (NSCLC) patients are often complicated by other respiratory diseases, including interstitial pneumonia (IP), chronic obstructive pulmonary disease (COPD), and pulmonary tuberculosis (TB), and the management of which can be problematic. NSCLC patients with IP sometimes develop fatal acute exacerbation induced by pharmacotherapy, and the establishment of a safe treatment strategy is desirable. For advanced NSCLC with IP, carboplatin plus nanoparticle albumin-bound paclitaxel is a relatively safe and effective first-line treatment option. Although the safety of immune checkpoint inhibitors (ICIs) for these populations remains controversial, ICIs have the potential to provide long-term survival. The severity of COPD is an important prognostic factor in NSCLC patients. Although COPD complications do not necessarily limit treatment options, it is important to select drugs with fewer side effects on the heart and blood vessels as well as the lungs. Active TB is complicated by 2-5% of NSCLC cases during their disease course. Since pharmacotherapy, especially ICIs, reportedly induces the development of TB, the possibility of developing TB should always be kept in mind during NSCLC treatment. To date, there is no coherent review article on NSCLC with these pulmonary complications. This review article summarizes the current evidence and discusses future prospects for treatment strategies for NSCLC patients complicated with IP, severe COPD, and TB.

Predicting epidermal growth factor receptor mutations in non-small cell lung cancer through dual-layer spectral CT: a prospective study

ObjectiveTo determine whether quantitative parameters of detector-derived dual-layer spectral computed tomography (DLCT) can reliably identify epidermal growth factor receptor (EGFR) mutation status in patients with non-small cell lung cancer (NSCLC).MethodsPatients with NSCLC who underwent arterial phase (AP) and venous phase (VP) DLCT between December 2021 and November 2022 were subdivided into the mutated and wild-type EGFR groups following EGFR mutation testing. Their baseline clinical data, conventional CT images, and spectral images were obtained. Iodine concentration (IC), iodine no water (INW), effective atomic number (Zeff), virtual monoenergetic images, the slope of the spectral attenuation curve (λHU), enhancement degree (ED), arterial enhancement fraction (AEF), and normalized AEF (NAEF) were measured for each lesion.ResultsNinety-two patients (median age, 61 years, interquartile range [51, 67]; 33 men) were evaluated. The univariate analysis indicated that IC, normalized IC (NIC), INW and ED for the AP and VP, as well as Zeff and λHU for the VP were significantly associated with EGFR mutation status (all p < 0.05). INW(VP) showed the best diagnostic performance (AUC, 0.892 [95% confidence interval {CI}: 0.823, 0.960]). However, neither AEF (p = 0.156) nor NAEF (p = 0.567) showed significant differences between the two groups. The multivariate analysis showed that INW(AP) and NIC(VP) were significant predictors of EGFR mutation status, with the latter showing better performance (p = 0.029; AUC, 0.897 [95% CI: 0.816, 0.951] vs. 0.774 [95% CI: 0.675, 0.855]).ConclusionQuantitative parameters of DLCT can help predict EGFR mutation status in patients with NSCLC.Critical relevance statementQuantitative parameters of DLCT, especially NIC(VP), can help predict EGFR mutation status in patients with NSCLC, facilitating appropriate and individualized treatment for them.Key PointsDetermining EGFR mutation status in patients with NSCLC before starting therapy is essential.Quantitative parameters of DLCT can predict EGFR mutation status in NSCLC patients.NIC in venous phase is an important parameter to guide individualized treatment selection for NSCLC patients.Graphical

Study on the Mechanism of Competing Endogenous Network of 'Scutellaria barbata D.Don-Houttuynia cordata- Radix Scutellariae' in the Treatment of NSCLC based on Bioinformatics, Molecular Dynamics and Experimental Verification.

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. Traditional Chinese medicine, known for its multi-target and multi-pathway characteristics, offers a potential treatment approach for NSCLC. This study aimed to explore the mechanism of the competitive endogenous network of 'Scutellaria barbata D.Don-Houttuynia cordata-Radix Scutellariae' in treating NSCLC through bioinformatics analysis and in vitro experiments. Various databases and ceRNA networks were utilized to collect and screen components and target genes, molecular docking and molecular dynamics simulations to determine the binding ability of ligand-receptor complexes. In vitro experiments were conducted to validate the effects of active ingredients of 'Scutellaria barbata D.Don-Houttuynia cordata- Radix Scutellariae' on non-small cell lung cancer cell line A549. The key target proteins CCL2, EDN1, MMP9, PPARG, and SPP1 were docked well with their corresponding TCM ligands. Among the ligand-receptor complexes, MMP9-Luteolin and MMP9-Quercetin demonstrated the weaking binding force, while the SPP1-Quercetin complex, associated with NSCLC prognosis, exhibited stable structure formation through hydrogen bond interaction during MD simulation. In vitro experiments confirmed the inhibitory effect of Quercetin on SPP1 expression, as well as the proliferation and migration of A549 cells. The findings suggest that 'Scutellaria barbata D.Don-Houttuynia cordata-Radix Scutellariae' may potentially treat lung cancer by suppressing the expression of SPP1. This study provides valuable insights and novel research directions for understanding the mechanism of traditional Chinese medicine in combating lung cancer.

Evolving Strategies in NSCLC Care: Targeted Therapies, Biomarkers, Predictive Models, and Patient Management

Abstract: Lung cancer, primarily Non-Small Cell Lung Cancer (NSCLC), is a global public health concern responsible for 80-85% of cases, with over two million new cases occurring annually, and 50% of them in Asia. While there has been a gradual reduction in United States (US) cases over the last decade, with 238,340 new cases and 127,070 deaths reported in 2023, managing metastatic NSCLC remains crucial, focusing on prolonging survival and enhancing quality of life. Integration of early palliative care shows promise in this regard. International guidelines recommend personalized treatment guided by genetic mutations (Epidermal Growth Factor Receptor (EGFR), Anaplastic Lymphoma Kinase, C-Ros oncogene [1ROS1]) and systemic therapies, including chemotherapy, targeted therapy, and immunotherapy, which play pivotal roles in redefining care. Treatment effectiveness hinges on factors such as cancer stage, patient health, and therapy type, with surgery and radiation therapy common in early stages and advanced stages requiring chemotherapy, targeted therapy, or immunotherapy. Despite advancements in treatment modalities, NSCLC continues to pose a significant challenge globally, particularly in Asia, where a substantial portion of new cases arise. While there has been an uncertain reduction in the incidence of lung cancer in the US over the past decade, the burden of the disease persists, with substantial mortality rates reported annually. Additionally, upon diagnosis, many NSCLC patients present with distant metastases, necessitating effective treatment strategies to improve overall survival and quality of life. The objectives include investigating targeted treatments for NSCLC with specific genetic mutations, examining mechanisms of novel therapies under study, evaluating preclinical and clinical studies for therapy efficacy and safety, identifying genetic and epigenetic biomarkers for diagnosis, prognosis, and treatment selection, developing predictive models for lung cancer recurrence and survival, assessing the efficacy of treatment approaches for early-stage lung cancer, and enhancing patient outcomes through collaborative care and lifestyle interventions. These collective efforts promise to improve patient outcomes and quality of life in the battle against NSCLC.

LncRNA KTN1-AS1 Drives Tumor Progression in Non-Small Cell Lung Cancer through microRNA-153-3p/KLF5 Axis

IntroductionThe most typical kind of lung cancer is non-small cell lung cancer (NSCLC). Surgery, targeted therapy, chemotherapy, and immunotherapy are all options for the treatment of NSCLC. LncRNA KTN1-AS1 is significantly increased in NSCLC, and it modulates the expression of microRNAs and downstream genes, promoting NSCLC progression.Material and methodsTCGA was employed to predict lncRNA KTN1-AS1 expression in NSCLC. The starBase was utilized to predict downstream microRNAs of KTN1-AS1. The RNA22 database was employed to predict corresponding binding sites. Subcellular localization of KTN1-AS1 was forecasted using the lncLocator database, and the results were validated by FISH. qRT-PCR was used to test KTN1-AS1, microRNA-153-3p, and KLF5 expression. CCK-8, flow cytometry, and Transwell were used to determine cell viability, proliferation, migration, and invasion. Western blot was used to test KLF5 and Ki67 protein levels, and dual-luciferase assay was used to assess bindings of KTN1-AS1 with microRNA-153-3p, and KLF5 with microRNA-153-3p.ResultsKTN1-AS1 was significantly upregulated in NSCLC cells. Silencing KTN1-AS1 significantly repressed the proliferation, migration, and invasion of NSCLC cells. KTN1-AS1 bound to microRNA-153-3p, and KLF5 was a direct target of microRNA-153-3p. Inhibition of microRNA-153-3p or overexpression of KLF5 restored the stimulatory impact of KTN1-AS1 knockdown on NSCLC cell proliferation and migration.ConclusionsKTN1-AS1 drove proliferation, migration, and invasion of NSCLC cells by regulating microRNA-153-3p/KLF5 axis. By studying the role of the KTN1-AS1/microRNA-153-3p/KLF5 axis in NSCLC, the possibility of targeting this axis as a therapeutic target in NSCLC can be explored.

Non-small Cell Lung Cancer Treatment: Current Status of Drug Repurposing and Nanoparticle-based Drug Delivery Systems

Non-small Cell Lung Cancer Treatment: Current Status of Drug Repurposing and Nanoparticle-based Drug Delivery Systems

Pseudolaric acid B suppresses NSCLC progression through the ROS/AMPK/mTOR/autophagy signalling pathway

Pseudolaric acid B (PAB), an acid isolated from the roots of Pseudolarix kaempferi gorden, has shown antitumour effects through multiple mechanisms of action. The objective of this study was to investigate the anticancer effect of PAB on non-small cell lung cancer (NSCLC) and its underlying mechanism. In our experiments, we observed that PAB decreased cell viability, inhibited colony formation, induced cell cycle arrest, impeded scratch healing, and increased apoptosis in H1975 and H1650 cells. Additionally, PAB treatment enhanced the fluorescence intensity of MDC staining in NSCLC cells, upregulated the protein expression of microtubule-associated protein light chain 3 II (LC3 II), and downregulated the expression of sequestosome 1 (SQSTM1/P62). Combined treatment with PAB and chloroquine (CQ) increased the protein expression levels of LC3 II and P62 while decreasing the apoptosis of H1975 and H1650 cells. Moreover, treatment with PAB led to significant mTOR inhibition and AMPK activation. PAB combined with compound C (CC) inhibited autophagy and apoptosis. Furthermore, PAB treatment increased intracellular reactive oxygen species (ROS) levels in NSCLC cells, which correlated with the modulation of the AMPK/mTOR signalling pathway and was associated with autophagy and apoptosis. Finally, we validated the antitumour growth activity and mechanism of PAB in vivo using athymic nude mice bearing H1975 tumour cells. In conclusion, our findings suggest that PAB can induce apoptosis and autophagic cell death in NSCLC through the ROS-triggered AMPK/mTOR signalling pathway, making it a promising candidate for future NSCLC treatment.

Elucidating the mechanism of action of Isobavachalcone induced autophagy and apoptosis in non-small cell lung cancer by network pharmacology and experimental validation methods

BackgroundLung cancer is the leading cause of cancer deaths, and non-small cell lung cancer (NSCLC) accounts for the majority of lung cancer-related mortality. In recent years, there have been numerous treatments for non-small cell lung cancer, but the cure and survival rates are still extremely low. Isobavachalcone (IBC) belongs to the chalcone component of the traditional Chinese medicine Psoralea corylifolia L., and is a unique Protein kinase B (AKT) pathway inhibitor with significant anticancer effects. Previous studies have shown that IBC possess a variety of biological properties, including anti-cancer, anti-inflammatory, and antioxidant properties. This study focused on the use of network pharmacology analysis, molecular docking technology and experimental validation to elucidate the potential mechanisms of IBC for the treatment of NSCLC. MethodsScreening key genes and pathways of IBC action in NSCLC using network pharmacology. The IBC target genes were from The Encyclopedia of Traditional Chinese Medicine (ETCM) and BATMAN-TCM databases, the NSCLC target genes were from GeneCards, Online Mendelian Inheritance in Man (OMIM) and The Therapeutic Target database (TTD) databases, both of which were taken as intersecting genes for protein–protein interaction network analysis and enrichment analysis, and the binding energies of the compounds to the core targets were further verified by molecular docking. Cell lines in vitro experiments were then performed to further unravel the mechanism of IBC for NSCLC. ResultsA total of 279 potential targets were retrieved by searching the intersection of IBC and NSCLC targets. Protein-protein interaction (PPI) network analysis indicated that 6 targets, including AKT1, RXRA, NCOA1, RXRB, RARA, PPARG were hub genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that IBC treatment of NSCLC mainly involves steroid binding, transcription factor activity, Pathways in cancer, cAMP signaling pathway, Adenosine 5‘-monophosphate (AMP)-activated protein kinase (AMPK) signaling pathway. Among them, the AMPK signaling pathway, which contained the largest number of enriched genes, may play a greater role in the treatment of NSCLC. Then, the results of in vitro experiment indicated that IBC could inhibit proliferation of NSCLC cells and induce cell autophagy and apoptosis. The results also showed that IBC could increase the protein expression of AMPK and decrease the protein expression of AKT and mammalian target of rapamycin (mTOR), suggesting that IBC can treat NSCLC by inducing cellular autophagy and apoptosis as well as modulating AMPK and AKT signaling pathways. ConclusionsIn summary, this study provided a new insight into the protective mechanism of IBC against NSCLC through network pharmacology and experimental validation.

Identifying the Multitarget Pharmacological Mechanism of Action of Genistein on Lung Cancer by Integrating Network Pharmacology and Molecular Dynamic Simulation.

Food supplements have become beneficial as adjuvant therapies for many chronic disorders, including cancer. Genistein, a natural isoflavone enriched in soybeans, has gained potential interest as an anticancer agent for various cancers, primarily by modulating apoptosis, the cell cycle, and angiogenesis and inhibiting metastasis. However, in lung cancer, the exact impact and mechanism of action of genistein still require clarification. To provide more insight into the mechanism of action of genistein, network pharmacology was employed to identify the key targets and their roles in lung cancer pathogenesis. Based on the degree score, the hub genes AKT1, CASP3, EGFR, STAT3, ESR1, SRC, PTGS2, MMP9, PRAG, and AR were significantly correlated with genistein treatment. AKT1, EGFR, and STAT3 were enriched in the non-small cell lung cancer (NSCLC) pathway according to Kyoto Encyclopedia of Genes and Genomes analysis, indicating a significant connection to lung cancer development. Moreover, the binding affinity of genistein to NSCLC target proteins was further verified by molecular docking and molecular dynamics simulations. Genistein exhibited potential binding to AKT1, which is involved in apoptosis, cell migration, and metastasis, thus holding promise for modulating AKT1 function. Therefore, this study aimed to investigate the mechanism of action of genistein and its therapeutic potential for the treatment of NSCLC.

Targeting KRASG12C in Non-Small-Cell Lung Cancer: Current Standards and Developments.

Among the most common molecular alterations detected in non-small-cell lung cancer (NSCLC) are mutations in Kristen Rat Sarcoma viral oncogene homolog (KRAS). KRAS mutant NSCLC is a heterogenous group of diseases, different from other oncogene-driven tumors in terms of biology and response to therapies. Despite efforts to develop drugs aimed at inhibiting KRAS or its signaling pathways, KRAS had remained undruggable for decades. The discovery of a small pocket in the binding switch II region of KRASG12C has revolutionized the treatment of KRASG12C-mutated NSCLC patients. Sotorasib and adagrasib, direct KRASG12C inhibitors, have been approved by the US Food and Drug Administration (FDA) and other regulatory agencies for patients with previously treated KRASG12C-mutated NSCLC, and these advances have become practice changing. However, first-line treatment in KRASG12C-mutated NSCLC does not differ from NSCLC without actionable driver genomic alterations. Treatment with KRASG12C inhibitors is not curative and patients develop progressive disease, so understanding associated mechanisms of drug resistance is key. New KRASG12C inhibitors and several combination therapy strategies, including with immune checkpoint inhibitors, are being studied in clinical trials. The aim of this review is to explore the clinical impact of KRAS, and outline different treatment approaches, focusing on the novel treatment of KRASG12C-mutated NSCLC.