Is GSH Chelated Pt Molecule Inactive in Anti‐Cancer Treatment? A Case Study of Pt₆GS₄

Abstract

Platinum (Pt) drugs are widely used in anti-cancer treatment although many reports advocated that tumor cells could inactivate Pt drugs via glutathione-Pt (GSH-Pt) adducts formation. To date, GSH chelated Pt molecules have not been assessed in cancer treatment because GSH-Pt adducts are not capable of killing cancer cells, which is widely accepted and well followed. In this report, endogenous biothiol is utilized to precisely synthesize a GSH chelated Pt molecule (Pt₆ GS₄ ). This Pt₆ GS₄ molecule can be well taken up by aggressive triple negative breast cancer (TNBC) cells. Subsequently, its metabolites could enter nuclei to interact with DNA, finally the DNA-Pt complex triggers TNBC cell apoptosis via the p53 pathway. Impressively, high efficacy for anti-cancer treatment is achieved by Pt₆ GS₄ both in vitro and in vivo when compared with traditional first-line carboplatin in the same dosage. Compared with carboplatin, Pt₆ GS₄ keeps tumor bearing mice alive for a longer time and is non-toxic for the liver and kidneys. This work opens a route to explore polynuclear Pt compound with accurate architecture for enhancing therapeutic effects and reducing systemic toxicity.