Triptonide Restore Cisplatin Sensitivity in Drug-Resistant Gastric Cancer Cells by Inhibiting Protective Autophagy

Abstract

Background: Autophagy is a key mechanism that contributes to the resistance to cisplatin (DDP), a natural bioactive medicinal compound extracted from traditional Chinese medicinal herb Tripterygium Wilfordii, in gastric cancer (GC). In this study, we assessed the effect of Triptonide to regulate autophagy and DDP resistance in GC. Method: DDP resistant GC cells was established to assess the effect of Triptonide alone or in combination with cisplatin on a variety of tumor assays. The cell viability and apoptosis/cell cycle were determined using Cell Counting Kit-8 (CCK-8) assay and flow cytometry. Autophagy level and the effect of Triptonide were evaluated using fluorescence intensity of RFP (red fluorescent protein)-GFP (green fluorescent protein)-LC3 (tandem fluorescent-tagged)/GFP-LC3, western blot, and electron microscope. Finally, the effect of Triptonide on chemosensitivity of the cisplatin-resistant cell line was validated in vivo on 32 nude mice. Results: The results showed that Triptonide not only led to a dose-dependent reduction in GC cell proliferation, it also reversed the chemoresistance of DDP-resistant on GC cell lines. We also found that autophagy was activated in DDP-resistant GC cancer cells during chemotherapy and contributed to the adaptative protective effects against DDP. Non-toxic dose of Triptonide act synergistically with DDP. Triptonide could inhibit the protective autophagy activation and enhance the sensitivity of DDP to DDP-resistant on GC cells. Triptonide effect on GC cells was also observed in nude mice. Conclusions: Based on these findings, we conclude that DDP in combination with Triptonide could restore DDP sensitivity in DDP-resistant on GC cells by inhibiting autophagy. Clinically, this combination might be effective in reversing chemoresistance.