The novel platinum(IV) prodrug of cisplatin axially conjugated with cannabidiol induces mitochondrial dysfunction and synergistically enhances anti-tumor effects

Classical cisplatin-based chemotherapeutic drugs are widely used in clinical practice. In recent years, novel platinum-based antitumor drugs have focused on replacing classical cisplatin-like Pt(II) complexes with relatively inert Pt(IV) prodrugs to overcome drug resistance and reduce toxic side effects. Based on the excellent physiological and pharmacological activities of cannabidiol (CBD), this study designed and synthesized novel Pt(IV) prodrugs W1-W6, which are axial conjugates of cisplatin with CBD and specific active small molecules. These prodrugs demonstrated more significant antitumor activity against tested tumor cell lines. Among them, the multifunctional Pt(IV) prodrug W5, conjugated with CBD and the PDK inhibitor DCA, exhibited excellent activity against both platinum-sensitive and cisplatin-resistant tumor strains. The IC₅₀ value of W5 for the A549R tumor strain was 8.53 ± 0.76 μM, significantly higher than that of the cisplatin group and 3.64 times the activity of CBD alone, demonstrating strong synergistic antitumor activity and potential to overcome cisplatin resistance. W5 is reduced by GSH in A549R cells, releasing CBD and Pt(II). Pt(II) binds to DNA, inducing damage and inhibiting repair, while CBD activates pro-apoptotic proteins, leading to mitochondrial dysfunction. Simultaneously, W5 reduces the levels of ROS scavengers, triggering endoplasmic reticulum dysfunction. These three mechanisms synergistically promote tumor cell apoptosis and overcome drug resistance. This design integrates multiple mechanisms through axial functionalization, breaking through the limitation of traditional platinum drugs targeting DNA alone, and achieves synergistic effects by regulating metabolism and intervening in the immune microenvironment.