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Leveraging platinum-protein interactions to overcome chemoresistance
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Journal Article
Leveraging platinum-protein interactions to overcome chemoresistance
2025
Overview
A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, enabling the removal of cytotoxic agents, such as anthracycline drugs. However, platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, we design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone. These drug conjugates retain the anticancer activity of anthracyclines and exhibit the ability to both circumvent drug efflux and delay the acquisition of drug resistance. In vivo experiments demonstrate that such drug conjugates extend survival in a preclinical organoid-based model of metastatic colon cancer in mice. Mechanistic studies indicate that these drug conjugates overcome resistance through covalent platinum-protein interactions, leading to significantly improved drug retention and alteration of subcellular drug distribution. This application of platinum offers many opportunities to confront issues related to chemoresistance and alternative pathways for augmenting conventional chemotherapeutics.
A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/106
/ 13/107
/ 13/31
/ 13/89
/ 14/19
/ 14/63
/ 140/131
/ 140/58
/ 42/35
/ 64/60
/ 82/29
/ Animals
/ Antineoplastic Agents - chemistry
/ Antineoplastic Agents - pharmacology
/ Colonic Neoplasms - drug therapy
/ Colonic Neoplasms - metabolism
/ Colonic Neoplasms - pathology
/ Design
/ DNA
/ Drug Resistance, Neoplasm - drug effects
/ Efflux
/ Humanities and Social Sciences
/ Humans
/ Ligands
/ Mice
/ Organoplatinum Compounds - chemistry
/ Organoplatinum Compounds - pharmacology
/ Platinum
/ Proteins
/ Pumps
/ Sarcoma
/ Science
/ Warheads
