Pt(IV) Prodrug as a Potential Antitumor Agent with APE1 Inhibitory Activity

The
base excision repair (BER) pathway is essential for cancer
cells to resist chemotherapeutic treatment, but its significance is
underrated. The present study describes a novel Pt­(IV) prodrug, AP1, targeting a critical BER protein, apurinic/apyrimidinic
endonuclease 1 (APE1). AP1 induces intracellular accumulation
of platinum and activates DNA damage response and apoptosis signals. AP1 can strongly inhibit the growth of malignant cells, including
cisplatin-resistant cancer cells, with up to 18.11 times inhibition
compared with cisplatin. Moreover, it is as toxic to normal cells
as cisplatin. In a xenograft model, AP1 is 3.86-fold
more potent than cisplatin without adverse effects. Intriguingly, AP1 can directly inhibit the AP endonuclease activity of APE1,
leading to an interruption of miRNA processing and upregulation of
the tumor suppressor PTEN. Our findings shed light on a mode of Pt­(IV)
interaction with a target protein and highlight the critical role
of BER in platinum-based cancer treatment.