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Issue 18, 2018
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Triple action Pt(IV) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

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Abstract

A series of triple action Pt(IV) prodrugs was designed to test the hypothesis that multi-action compounds, where each bioactive moiety intervenes in several cellular processes, might be more effective than a single agent at killing cancer cells. In particular, “triple action” Pt(IV) derivatives of cisplatin, where the axial ligands are inhibitors of cyclooxygenase (COXi), histone deacetylase (HDACi) or pyruvate dehydrogenase kinase (PDKi) were developed. All compounds, ctc-[Pt(NH3)2(COXi)(PDKi)Cl2], ctc-[Pt(NH3)2(COXi)(HDACi)Cl2] and ctc-[Pt(NH3)2(HDACi)(PDKi)Cl2], where COXi = aspirin or ibuprofen, PDKi = dichloroacetate and HDACi = valproate or phenylbutyrate, were significantly more cytotoxic than cisplatin against all cell lines of an in-house panel of human cancer cells. They were particularly effective against thyroid and pancreatic cancer cells in monolayer cytotoxicity tests. Remarkably, in 3D spheroid cancer cell cultures, some triple action compounds showed an antitumor potency up to 50-fold higher than cisplatin against a KRAS mutated pancreatic cancer cell line (PSN-1 cells). Standard biochemical assays classically employed to explore structure activity relationships of platinum drugs, such as cellular uptake and binding to potential biological targets (DNA, HDAC, mitochondria, and COX), do not provide linear correlations with the overall cytotoxicity data. We observed a preferential induction of ROS production and of an anti-mitochondrial effect in cancer cells compared to rapidly dividing non-cancerous cells. Thus, we propose that these new triple action Pt(IV) derivatives of cisplatin are a novel and interesting class of potent and selective cytotoxic agents.

Graphical abstract: Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

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Publication details

The article was received on 26 Jan 2018, accepted on 07 Apr 2018 and first published on 24 Apr 2018


Article type: Edge Article
DOI: 10.1039/C8SC00428E
Citation: Chem. Sci., 2018,9, 4299-4307
  • Open access: Creative Commons BY-NC license
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    Triple action Pt(IV) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance

    E. Petruzzella, R. Sirota, I. Solazzo, V. Gandin and D. Gibson, Chem. Sci., 2018, 9, 4299
    DOI: 10.1039/C8SC00428E

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