Acyclic Retinoid Inhibits the EGFR/AKT Signaling Pathway and Cancels Cisplatin-resistant Cell Characteristics

Background/Aim: Lung cancer is among the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Overactivation of the EGFR/AKT signaling pathway contributes significantly to NSCLC progression and metastasis. Cisplatin, a widely used chemotherapeutic agent, faces limitations due to severe side effects and the emergence of resistant cancer cells. Acyclic retinoid (ACR), a synthetic derivative of vitamin A, has shown antitumor effects in hepatocellular carcinoma, but its efficacy against NSCLC and cisplatin-resistant cells remains unclear. This study aimed to investigate whether ACR could inhibit EGFR/AKT signaling and enhance therapeutic efficacy against NSCLC and cisplatin-resistant cells. Materials and Methods: Human NSCLC A549 cells, cisplatin-resistant A549 (A549CR) cells, and normal lung epithelial BEAS-2B cells were treated with ACR, alone or in combination with cisplatin. Cell viability, apoptosis, and changes in expression/phosphorylation of EGFR, AKT, and cell cycle regulators were assessed using cell viability assay, immunostaining, and immunoblotting. Results: ACR selectively reduced viability of A549 cells with less toxicity to BEAS-2B cells and induced apoptosis via cleaved Caspase-3 activation. ACR inhibited EGFR/AKT signaling and up-regulated p27^KIP1 in A549 cells. The combination of ACR and cisplatin synergistically reduced cell viability and suppressed AKT phosphorylation. Notably, ACR also inhibited EGFR/AKT signaling in A549CR cells, restoring sensitivity to cisplatin and reversing EMT-like characteristics. Conclusion: ACR effectively inhibits EGFR/AKT signaling and enhances cisplatin sensitivity in NSCLC and cisplatin-resistant cells, suggesting its potential as a promising therapeutic strategy for lung cancer.