Discovery of a Novel EF24 Analogue-Conjugated Pt(IV) Complex as Multi-Target Pt(IV) Prodrugs Aims to Enhance Anticancer Activity and Overcome Cisplatin Resistance

Acquired resistance in cancer remains a significant challenge
in
oncology, posing obstacles to the efficacy of diverse therapeutic
approaches. The nuclear factor-kappa B (NF-κB) signaling pathway
plays an important role in the development of drug resistance in tumor
cells. Herein, we employed NF-κB inhibitors and cisplatin to
synthesize multitarget Pt(IV) antitumor prodrugs. Among them, the
antiproliferation activity of complex 8 demonstrated
a remarkable 146.92-time increase compared to cisplatin against A549/CDDP
cells. Moreover, complex 8 could effectively induce DNA
damage, promote ROS generation, induce autophagy, trigger the mitochondrial
apoptosis pathway, and suppress cell proliferation through the NF-κB
signaling pathway. Furthermore, complex 8 effectively
downregulated the levels of VEGF and HIF-1α and exerted antiproliferative
activity through the PI3K/AKT and STAT-3 pathway in A549/CDDP cells.
Interestingly, complex 8 showed a superior in vivo antitumor
activity than cisplatin, 5a, or their combination, suggesting
its potential as a promising candidate for further drug development
in lung cancer treatment.