Narciclasine as a Novel Treatment for Lung Cancer and Malignant Pleural Mesothelioma: Insights from 3D Tumor Spheroid Models

Our plain-English summary of Narciclasine as a Novel Treatment for Lung Cancer and Malignant Pleural Mesothelioma: Insights from 3D Tumor Spheroid Models, by S. Jiang, S. Berkcan, N. Perriraz-Mayer, et al (International Journal of Molecular Sciences, 2025).

The study

• Authors: S. Jiang, S. Berkcan, N. Perriraz-Mayer, F. Triponez, V. Serre-Beinier
• Journal: International Journal of Molecular Sciences
• Published: 2025;26(20)
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Thoracic tumors, including lung adenocarcinoma (LUAD) and malignant pleural mesothelioma (MM), remain a leading cause of cancer-related deaths, primarily due to the challenges in treating advanced thoracic tumors. New drugs with optimal efficacy and minimal side effects are required. Traditional Chinese Medicine (TCM) compounds offer a promising alternative. Our study explores the effectiveness of the TCM compound Narciclasine against LUAD and MM. Spheroids derived from LUAD (A549, LuCa1) and MM (MSTO-211H, H2052/484) cell lines were treated with Narciclasine, and efficacy was evaluated through cell morphology analysis, intracellular adenosine triphosphate (ATPi) and lactate dehydrogenase (LDH) assays, RT-qPCR, and western blot analysis. Narciclasine reduced cell viability, with an 80% reduction in viability in MM. It induced cell apoptosis and inhibited proliferation. The IC50 values for Narciclasine ranged from 50 to 150 nM. In silico analysis identified shared gene targets between Narciclasine, LUAD, and MM. Narciclasine modulated the expression of genes associated with ferroptosis and cuproptosis, and the epithelial-to-mesenchymal transition. Narciclasine shows promising efficacy against LUAD and MM spheroid models. These findings warrant further investigation into the mechanisms of action and potential clinical application of Narciclasine for treating thoracic malignancies, offering hope for improved therapeutic options and patient outcomes.

In plain English

This was a laboratory study of cancer cells. It did not study people or asbestos exposure. Researchers in Geneva grew two lung adenocarcinoma cell lines (A549, LuCa1) and two malignant pleural mesothelioma cell lines (MSTO-211H, H2052/484) as three-dimensional cell clusters called spheroids. They treated them for 72 hours with narciclasine, a Traditional Chinese Medicine plant compound, at 12.5 to 800 nM. Mesothelioma spheroids changed shape at lower concentrations than lung adenocarcinoma spheroids. The concentrations that produced half the maximal effect on viability or metabolism ranged from 46 to 166 nM. The authors reported up to 80–85% lower viability in mesothelioma spheroids, compared with 50% in A549 spheroids. At 50 nM, apoptosis (programmed cell death) increased in MSTO-211H and LuCa1 spheroids but not significantly in the other two lines. At 50 nM, the drug changed the expression of some marker genes associated with iron- and copper-dependent cell death pathways and with the epithelial-to-mesenchymal transition. A computer analysis predicted 61 gene targets shared by both cancers. The authors concluded that narciclasine shows promise and warrants further study. They plan to test its toxicity on non-cancerous lung cells.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on 3D tumor spheroids grown from human cancer cell lines, plus a computer-based (network pharmacology) analysis of predicted gene targets
• Who was studied: Four human cancer cell lines, studied at Geneva University Hospitals. Two were lung adenocarcinoma lines: A549 (purchased) and LuCa1 (established in the laboratory from a 79-year-old woman with untreated stage IV lung adenocarcinoma). Two were malignant pleural mesothelioma lines: MSTO-211H (purchased) and H2052/484 (derived in the laboratory from H2052 cells grown as a tumor in athymic mice).
• Exposure: The drug narciclasine at increasing concentrations (12.5 nM to 800 nM) for 72 hours. Most experiments on mechanism used 50 nM. No asbestos or fiber exposure was studied.
• Main results:
  • Mesothelioma spheroids showed clear shape changes at lower concentrations: MSTO-211H from 25 nM and H2052/484 from 50–100 nM. Lung adenocarcinoma spheroids (A549 and LuCa1) showed only slight reductions in size.
  • In mesothelioma spheroids, IC50 values were 81 nM (MSTO-211H) and 166 nM (H2052/484) for cell viability by LDH assay, and 46 nM (MSTO-211H) and 83 nM (H2052/484) for ATP metabolism.
  • In lung adenocarcinoma spheroids, A549 had IC50 values of 145 nM (viability) and 121 nM (ATP metabolism). LuCa1 had an IC50 of 91 nM for ATP metabolism. The LDH test could not be used for LuCa1 cells.
  • The authors reported up to 80–85% reduction in viability in mesothelioma spheroids, compared with 50% in A549 spheroids.
  • Untreated mesothelioma spheroids had more proliferating (Ki67-positive) cells than untreated lung adenocarcinoma spheroids: 8.8% versus 2.2% (p less than 0.01). At 50 nM, LuCa1 showed a non-significant decrease (2.35% in controls versus 1.07% treated, p = 0.25). Treated mesothelioma spheroids showed no consistent change.
  • At 50 nM, apoptotic (TUNEL-positive) cells increased in MSTO-211H (3.90% untreated versus 11.67% treated, p = 0.0156) and in LuCa1 (2.74% versus 4.88%, p = 0.0156). There was no significant increase in A549 and H2052/484.
  • The computer analysis identified 308 potential narciclasine gene targets linked to lung cancer and 62 linked to mesothelioma, with 61 common to both.
  • The authors measured the expression of 19 marker genes associated with ferroptosis and cuproptosis pathways after 72 hours at 50 nM. In both mesothelioma cell lines, most of these markers were upregulated at the mRNA level. LIPT1 rose 3.8-fold in MSTO-211H and 4.5-fold in H2052/484. CAV-1 was downregulated (0.44-fold in MSTO-211H and 0.47-fold in H2052/484).
  • At the protein level, narciclasine did not significantly affect SLC7A5. DLAT protein was slightly reduced in three of the four cell lines despite increased mRNA.
  • The authors reported that treatment was associated with increased mRNA expression of SNAIL1, ZEB1/ZEB2 and CDH2 and decreased CDH1 (E-cadherin). This was seen in the lung adenocarcinoma spheroids; the mesothelioma cell lines showed mixed changes, and CDH1 could not be detected in either mesothelioma line.
• The authors' conclusion: The authors concluded that narciclasine shows promise against lung cancer and malignant pleural mesothelioma, even used alone. They suggested that at 50 nM it could be combined with other anti-cancer therapies, and said further investigation of its mechanism and possible clinical use is warranted.
• Limitations the authors state:
  • Increased apoptosis was not seen in all cell lines; the authors said larger data sets are needed.
  • Changes in cell-state (EMT) markers were measured only as mRNA; protein-level confirmation is needed.
  • The proposed role of DLAT needs confirmation by measuring its oligomerized form.
  • The LDH test could not be used to estimate the cytotoxic effect on LuCa1 cells, because control cells already showed LDH activity as high as the positive control.
  • Toxicity in non-cancerous lung cells has not yet been tested in this model; the authors plan to do so.
  • The authors attributed the moderate sensitivity of spheroids to narciclasine alone to the low concentration used.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Lung Cancer, Pleural Mesothelioma, Lung Adenocarcinoma, Lactate Dehydrogenase (LDH), Apoptosis.

Related studies

• Changes in global gene expression associated with 3D structure of tumors: an ex vivo matrix-free mesothelioma spheroid model — H. Kim, Y. Phung, et al. (2012)
• Analysis of Gene Expression in 3D Spheroids Highlights a Survival Role for ASS1 in Mesothelioma — D. Barbone, L. Van Dam, et al. (2016)
• 2-Deoxy-glucose Enhances the Effect of Cisplatin and Pemetrexed in Reducing Malignant Pleural Mesothelioma Cell Proliferation But Not Spheroid Growth — I. Gerogianni, E. Pitaraki, et al. (2019)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)
• Optimization of tumor spheroid model in mesothelioma and lung cancers and anti-cancer drug testing in H2052/484 spheroids — D.A.J. Gendre, E. Ameti, et al. (2021)
• The FAK inhibitor BI 853520 inhibits spheroid formation and orthotopic tumor growth in malignant pleural mesothelioma — V. Laszlo, Z. Valko, et al. (2019)

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