Enhancing the therapeutic efficacy of gambogenic acid by modulating the NRF2/HSF1/HO-1 signaling pathway in cisplatin-resistant lung cancer cells

Cisplatin is a cornerstone in cancer chemotherapy and chemoimmunotherapy protocols; however, the emergence of drug resistance poses a substantial challenge. Gambogenic acid (GNA), a natural compound derived from gamboge, has been documented to exert antitumor effects across a range of cancer types. Nonetheless, its clinical utilization is restricted by the necessity for high dosages to attain adequate bioactivity. In this study, we demonstrated that GNA could induce significant cell death in cisplatin-resistant A549/DDP cells. GNA treatment reduced NRF2 protein levels in A549/DDP cells, and both genetic and pharmacological inhibition of NRF2 further enhanced the cytotoxic effects of GNA. In addition, GNA treatment increased the expression of HO-1 through a mechanism independent of NRF2. Subsequent analyses indicated that GNA treatment elicited a heat-shock response, particularly in cells with NRF2 knockdown. While baseline HO-1 expression in A549/DDP cells is regulated by NRF2, the upregulation of HO-1 induced by GNA is dependent on HSF1, a key regulator of the heat-shock response. Furthermore, although treating cells with HO-1 inhibitors alone did not affect the viability of A549/DDP cells, it dramatically enhanced the GNA-induced cell death in combinational therapy. Collectively, our findings demonstrated that GNA possesses substantial cytotoxic activity in cisplatin-resistant lung cancer cells, and the effect can be augmented by disrupting the NRF2 and HSF1 signaling pathways, which jointly promote HO-1 expression in cells coping with GNA-induced acute stress. This study underscores a novel mechanism underlying the anticancer activity of GNA and suggests a potential strategy to overcome the translational challenges of GNA in lung cancer therapy.