The combination of Xuefu Zhuyu decoction and osimertinib inhibits the proliferation of non-small cell lung cancer cells by activating endoplasmic reticulum stress

Background: To investigate the effects of the combination of XueFu ZhuYu (XFZY) decoction and osimertinib on the proliferation, apoptosis, migration, and endoplasmic reticulum stress (ERS) of non-small cell lung cancer (NSCLC) cell lines. Methods: Eight Sprague-Dawley (SD) rats were used to prepare XFZY serum. XFZY serum and osimertinib (separately or in combination) were used to treat NSCLC cells (H1975 cells and National Cancer Institute (NCI)-H1299 cells). Next, 5 mmol/L N-acetylcysteine (NAC) was treated with the XFZY serum + Osimertinib-induced NSCLC cells. Cell Counting Kit-8 (CCK8), flow cytometry, Transwell, and scratch assays were performed to detect the cell proliferation, apoptosis, migration, and invasion. Flow cytometry, Transmission Electron Microscopy (TEM), and Western Blot (WB) were performed to detect ERS levels in the cells. Results: Compared with the XFZY serum group or Osimertinib group, the XFZY serum + Osimertinib group significantly inhibited cell proliferation, migration, and invasion and promoted the apoptosis of NSCLC cells. Additionally, XFZY serum + Osimertinib induced endoplasmic reticulum (ER) expansion and mitophagy, significantly increasing Reactive oxygen species (ROS) accumulation, and upregulating the expression of ERS-related proteins, including Activating Transcription Factor 4 (ATF4), C/EBP Homologous Protein (CHOP), and phosphorylated PKR-like ER kinase (p-PERK). Interestingly, these responses were alleviated by NAC treatment. Limitations of this study arise from its focus on in vitro cell models data, without validation in clinical samples or in vivo environments. Conclusions: XFZY decoction increased the Osimertinib sensitivity of NSCLC cells by enhancing the ERS response and damaging the protection of the unfolded protein response (UPR) by activating the PERK-ATF4-CHOP signaling pathway.

Non-small cell lung cancers; Xuefu Zhuyu decoction; Osimertinib; Reactive oxygen species; Endoplasmic reticulum stress

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