Issue 5, 2015

Induction of targeted necrosis with HER2-targeted platinum(iv) anticancer prodrugs


It is well-recognized that the failure of many chemotherapeutics arises due to an inability to induce apoptosis. Most cancers acquire a myriad of pro-survival adaptations, and the vast heterogeneity and accumulation of multiple often unrelated anti-apoptotic signaling pathways have been a major stumbling block towards the development of conventional chemotherapeutics, which can overcome drug resistance. We have developed highly potent and selective HER2-targeted Pt(IV) prodrugs bearing anti-HER2/neu peptides that induce targeted necrosis as a novel strategy to circumvent apoptosis-resistance. These Pt(IV)–peptide conjugates exhibit a unique biphasic mode of cytotoxicity comprising rapid killing of cancer cells via necrosis in the first phase followed by an extended and gradual phase of delayed cell death. We demonstrate that these Pt(IV)–peptide prodrugs are more potent than their Pt(II) congeners in direct cell-killing and exhibit comparable long-term inhibition of proliferative capacity and with greater selectivity against HER2-positive cancer cells.

Graphical abstract: Induction of targeted necrosis with HER2-targeted platinum(iv) anticancer prodrugs

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Article information

Article type
Edge Article
03 Jan 2015
16 Mar 2015
First published
16 Mar 2015
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2015,6, 3051-3056

Induction of targeted necrosis with HER2-targeted platinum(IV) anticancer prodrugs

D. Y. Q. Wong, J. H. Lim and W. H. Ang, Chem. Sci., 2015, 6, 3051 DOI: 10.1039/C5SC00015G

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