Effects of Autophagy Inhibition by SAR405, a Selective VPS34 Inhibitor, on Pleural Mesothelioma Cells

Our plain-English summary of Effects of Autophagy Inhibition by SAR405, a Selective VPS34 Inhibitor, on Pleural Mesothelioma Cells, by Y. Kuwabara, K. Sakai, K. Shiraishi, et al (Thoracic Cancer, 2026).

The study

• Authors: Y. Kuwabara, K. Sakai, K. Shiraishi, I. Matsumoto, S. Ishii, S. Yokosuka, M. Abe, T. Takahashi, Y. Kawano, H. Nishimura, M. Toda-Sasaki, Y. Kobayashi-Ogawa, S. Kikuchi, Y. Hirata, H. Kyoyama, G. Moriyama, N. Koyama, K. Uematsu
• Journal: Thoracic Cancer
• Published: 2026;17(5):e70255
• Cited by: 1 article, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Background: Pleural mesothelioma is a highly aggressive malignancy with a poor prognosis due to the limited efficacy of currently available therapies. Macroautophagy (hereafter "autophagy") is a lysosome-mediated degradation pathway involved in cellular homeostasis that can either support or inhibit cancer progression depending on context. In this study, we investigated the effects of SAR405, an inhibitor of vacuolar protein-sorting 34 (VPS34), which is important for regulating the early stage of autophagy, on pleural mesothelioma.

Methods: Human pleural mesothelioma cell lines H28, H2452, and 211H were cultured with SAR405. The effects of SAR405 on protein expression, cell viability, colony formation, cell invasion, and the cell cycle were investigated, as were its synergistic effects with cisplatin. Autophagy induction was evaluated in mesothelioma cells transfected with the pMRX-IP-GFP-LC3-RFP-LC3ΔG plasmid, which was developed for the quantitative and statistical estimation of autophagy.

Results: SAR405 treatment alone significantly reduced cell viability, colony formation, and cell invasion, and increased G2/M cell cycle arrest. In addition, SAR405 induced apoptosis in the H2452 cell line. Although cisplatin weakly induced autophagy in mesothelioma cells, its combination with SAR405 did not result in additive or synergistic effects on cell viability.

Conclusions: Based on these results, inhibition of VPS34 by SAR405 effectively suppressed cell viability in all mesothelioma cell lines and induced apoptosis in H2452 cells. The findings of this study indicate the potential for VPS34 inhibition as a new strategy for the treatment of mesothelioma and provide insights into the complex role of autophagy in this malignancy.

© 2026 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.

In plain English

In this laboratory study, the authors treated three human pleural mesothelioma cell lines (H28, H2452 and 211H) with SAR405, an experimental drug that blocks autophagy, the process cells use to recycle their own material, by inhibiting a protein called VPS34. They also tested the chemotherapy drug cisplatin, alone and with SAR405. No asbestos exposure, patients or animals were studied. The authors read a fluorescent-marker change as showing SAR405 at 2.5 μM or more suppressed autophagy in all three lines. SAR405 alone significantly reduced cell survival and colony formation. It also slowed closure of a scratch in a cell layer, a movement test the authors called invasion. It increased the share of cells stalled at the G2/M stage. It triggered programmed cell death (apoptosis) in H2452 cells only. Cisplatin weakly induced autophagy. Adding SAR405 to cisplatin gave no additive or synergistic effect on cell survival. In three-dimensional cell clusters, 10 μM SAR405 left H28 clusters significantly smaller than controls; the other two lines showed only a non-significant trend. The authors concluded that VPS34 inhibition has potential as a new mesothelioma treatment strategy.

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 human pleural mesothelioma cell lines
• Who was studied: Three commercially obtained human pleural mesothelioma cell lines (211H, H2452 and H28) from the American Type Culture Collection. No patients or animals were studied.
• Exposure: No asbestos exposure was studied. The cells were exposed to the VPS34 inhibitor SAR405 and to cisplatin. In the cell-survival tests, each drug was used at 0.1 to 50 μM for 72 hours. SAR405 was also tested in combination with cisplatin.
• Main results:
  • SAR405 at 2.5 μM or higher increased the GFP to RFP fluorescence ratio in all three cell lines. The authors interpreted this as suppression of autophagy.
  • SAR405 alone significantly reduced cell viability and colony formation and increased G2/M cell cycle arrest in the mesothelioma cell lines. It also reduced what the authors call cell invasion, which they measured with a scratch wound healing assay.
  • In the scratch wound assay, which measured cell migration and motility as a wound closure rate, SAR405 (10.0 μM) significantly inhibited scratch wound closure by the pleural mesothelioma cells.
  • SAR405 induced apoptosis in the H2452 cell line.
  • SAR405 did not induce apoptosis in the H28 or 211H cell lines.
  • Cisplatin alone weakly induced autophagy. The GFP to RFP ratio decreased after 5.0 μM cisplatin in H28 and 211H cells and after 0.5 μM cisplatin in H2452 cells.
  • Combining cisplatin with SAR405 did not produce additive or synergistic effects on cell viability.
  • In a 3D spheroid (cell cluster) model, SAR405 at 10 μM significantly reduced spheroid size in the H28 cell line compared with the DMSO control. The authors describe this as inhibited spheroid expansion.
  • In H2452 and 211H spheroids, spheroid area tended to decrease with SAR405, but the change was not statistically significant.
• The authors' conclusion: The authors concluded that SAR405 suppressed cell viability in all the mesothelioma cell lines and induced apoptosis in H2452 cells. They stated that their findings indicate the potential for VPS34 inhibition as a new strategy for treating mesothelioma.
• Limitations the authors state:
  • The authors note that SAR405 has a relatively high IC50 (the concentration needed for a half-strength effect). They say combination strategies to enhance its effect are needed.
  • The authors note that SAR405 has poor hydrophilicity, limited stability and low bioavailability, which would require frequent or high-dose administration.
  • The authors state that the LC3B band was difficult to detect in all the cell lines. This made it difficult to evaluate cisplatin-induced changes in autophagy by western blotting, even with chloroquine.
  • The authors state that the mechanisms linking VPS34, autophagy and the cell cycle need further research.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Prognosis, Synergistic Effect, Cisplatin, Mesothelioma, Apoptosis.

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