Bufalin: a potential drug for regulating EGFR-TKIs resistance in lung cancer via the EGFR-PI3K/Akt-mTOR signaling.

BACKGROUND: Bufalin has shown potential in overcoming cancer resistance to osimertinib and sorafenib in epidermal growth factor receptor (EGFR)-mutated lung cancer. This study investigated the regulatory effect of bufalin on EGFR tyrosine kinase inhibitors (TKIs) resistance in lung cancer. METHODS: The cell experiments including the MTT assay, flow cytometry, and real-time polymerase chain reaction (RT-PCR) were used to determine the effects of bufalin and/or EGFR-TKIs gefitinib on the growth, proliferation, cycle, apoptosis, and expressions of genes linked to the EGFR-phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)-mammalian target of rapamycin (mTOR) signal pathway of human non-small cell lung cancer cell line H1975. In animal experiments, a model of H1975 cell subcutaneous graft tumor in severe combined immune deficiency (SCID) mice was created. Then bufalin and gefitinib were administered for three weeks by gavage and intraperitoneal injection, respectively. Tumor weight, volume, and other indicators were analyzed. In the meantime, RT-PCR and immunohistochemistry were performed to quantify key genes and proteins that were related to the EGFR-PI3K/Akt-mTOR signal pathway, including EGFR, PI3K, Akt, mTOR, 70 kDa ribosomal protein S6 kinase (p70S6K), and eukaryotic translation initiation factor 4E-binding protein (4E-BP) in tumor tissues of various intervention groups. RESULTS: Bufalin and gefitinib could control the cell cycle, induce apoptosis, and impede H1975 cell development and growth. Furthermore, bufalin and gefitinib inhibited the growth of lung cancer tumor and decreased the expression of proteins pertinent to the EGFR-PI3K/Akt-mTOR pathway, including EGFR, Akt, mTOR, and p70S6K. These effects were more pronounced in the combined intervention group. CONCLUSIONS: Bufalin can overcome gefitinib resistance in lung cancer by modulating the EGFR-PI3K/Akt-mTOR signaling pathway.