A Platinum(IV) Anticancer Prodrug Targeting Nucleotide Excision Repair To Overcome Cisplatin Resistance

Abstract

DNA damage response plays a key role not only in maintaining genome integrity but also in mediating the antitumor efficacy of DNA-damaging antineoplastic drugs. Herein, we report the rational design and evaluation of a Pt anticancer prodrug inhibiting nucleotide excision repair (NER), one of the most pivotal processes after the formation of cisplatin-induced DNA damage that deactivates the drug and leads to drug resistance in the clinic. This dual-action prodrug enters cells efficiently and causes DNA damage while simultaneously inhibiting NER to promote apoptotic response. The prodrug is strongly active against the proliferation of cisplatin-resistant human cancer cells with an up to 88-fold increase in growth inhibition compared with cisplatin, and the prodrug is much more active than a mixture of cisplatin and an NER inhibitor. Our study highlights the importance of targeting downstream pathways after the formation of Pt-induced DNA damage as a novel strategy to conquer cisplatin resistance.

Dinuclear Platinum(II) Complexes with Bone‐Targeting Groups as Potential Anti‐Osteosarcoma Agents

“…[12] In virtue of different structures and mechanisms, [13] polynuclear platinum complexes demonstrate great favorable properties as compared with mononuclear ones. [14] Recently,t argeted platinum drugs have witnessed improved tumor selectivity, [15] reduced side effects [16] and enhanced drug efficacy. [17] However, the design and application of targeted polynuclear platinum complexes for osteosarcoma are quite rare due to the lack of effective methodsfor preparation.…”

FerriIridium: A Lysosome‐Targeting Iron(III)‐Activated Iridium(III) Prodrug for Chemotherapy in Gastric Cancer Cells

“…[1] In recent years,new prodrugs that are activated by the tumor microenvironment have been developed. Important examples include those which are based on nitro [2] or azo groups, [3] which act efficiently in the hypoxic environment commonly found in solid tumors.Other prodrugs with glutathione-responsive, [4] H 2 O 2 -mediated release, [5] pH-triggered, [6] or HOCl-and formaldehyde-triggered mechanisms, [7] have also been reported. Many studies show apositive correlation between iron storage and the risk of cancer, including colorectal, liver, kidney,l ung,a nd stomach cancers.…”

Self‐assembled Lipid Nanoparticles for Ratiometric Codelivery of Cisplatin and siRNA Targeting XPF to Combat Drug Resistance in Lung Cancer

“…Moreover, the inhibition of DNA damage repair sensitizes c‐erhB‐2 overexpressed cancer cells to cisplatin . Within this frame, our group has reported a dual‐action platinum(IV) anticancer prodrug containing both a DNA damaging unit and a small‐molecule NER inhibitor, and the prodrug is proved to be significantly active in cisplatin‐resistant lung cancer cells . However, the potential unfavorable off‐target effect from the small‐molecule inhibitor is a concern.…”

“…[7] Within this frame, our group has reported ad ual-action platinum(IV) anticancer prodrug containing both aD NA damagingu nit and as mall-molecule NER inhibitor,a nd the prodrug is provedt o be significantly active in cisplatin-resistant lung cancer cells. [8] However, the potentialu nfavorable off-target effect from the small-molecule inhibitor is ac oncern. In addition, the ratio of platinum to the inhibitor is limited by the geometric property of the prodrug, leading to non-optimized inhibitory effect from the inhibitor.…”