Paeonol enhances a recombinant EGFR-targeted fusion protein-drug conjugate induced antitumor efficacy in esophageal cancer

Esophageal cancer (EC) is a gastrointestinal cancer with high morbidity and mortality, along with a low 5-year survival rate, which urgently requires the discovery of new drugs for prevention and treatment. Our previous studies have found a novel EGFR-targeted fusion protein-drug conjugate, Fv-LDP-D3-AE, which exhibits significant inhibitory activity against esophageal cancer. However, the effectiveness of monotherapy still faces major challenges in clinical translation for esophageal cancer treatment. Therefore, there is an urgent need to identify a candidate anti-tumor drug that can be combined with Fv-LDP-D3-AE to enhance therapeutic efficacy. In this study, we report a novel combination treatment regimen of paeonol with Fv-LDP-D3-AE, using human esophageal cancer cells KYSE70 and EC109 for in vitro studies and establishing a BALB/c nude mouse xenograft model for in vivo experiments to investigate the anti-tumor efficacy and potential mechanisms of the combination therapy in esophageal cancer. The results indicated that the combined treatment emerged a synergistic effect, which could effectively inhibit the proliferation, migration, and invasion of esophageal cancer cells, induce more obvious cell apoptosis and DNA damage, and suppress tumor growth in the xenograft mouse model with a tumor inhibition rate of 76%. This may be attributed to the combination therapy simultaneously inhibiting the EGFR/AKT/mTOR signaling pathway and downregulating the expression of nucleolin. Overall, these findings suggest that paeonol could synergize with Fv-LDP-D3-AE to enhance anti-esophageal cancer efficacy, which may be a promising therapeutic strategy for esophageal cancer.