A cisplatin-based platinum(IV) prodrug containing a glutathione s-transferase inhibitor to reverse cisplatin-resistance in non-small cell lung cancer.

A Pt(IV) prodrug of cisplatin containing a glutathione s-transferase (GSTs) inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol (NBDHEX), complex 1, was designed and studied aiming to overcome cisplatin-resistance and reduce its toxicity by inhibiting GSTs overexpressed in cancer cells. The complex could be reduced to release its active Pt(II) species and axial ligand in the presence of ascorbic acid. In cytotoxicity study, complex 1 showed more potent anticancer activity than cisplatin and NBDHEX against all the tested cancer cells, especially toward cisplatin resistant A549/DDP cells with a resistance factor value of 0.37. By effectively inhibiting GSTs, complex 1 was found to be able to promote higher platinum uptake and cause more severe DNA damage in both A549 cells and A549/DDP cells as compared with cisplatin. Further mechanism study indicated that it could trigger cell death via an apoptotic pathway. In vivo tests on A549 xenograft tumor mice model showed that complex 1 presented higher tumor inhibiting rate and lower toxicity than cisplatin as well. In all, the Pt(IV) prodrug has potential to be developed as an anticancer agent.