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

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.

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.

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.

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.