Triple action Pt(iv) derivatives of cisplatin: a new class of potent anticancer agents that overcome resistance† †Electronic supplementary information (ESI) available. See DOI: 10.1039/c8sc00428e

Content Provider	Semantic Scholar
Author	Petruzzella, Emanuele Sirota, Roman Solazzo, Irene Gandin, Valentina Gibson, Dan
Copyright Year	2018
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.
Starting Page	4299
Ending Page	4307
Page Count	9
File Format	PDF HTM / HTML
DOI	10.1039/c8sc00428e
PubMed reference number	29780561
Journal	Medline
Volume Number	9
Alternate Webpage(s)	https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/3a/cd/SC-009-C8SC00428E.PMC5944384.pdf
Alternate Webpage(s)	https://pubs.rsc.org/en/content/articlepdf/2018/sc/c8sc00428e?page=search
Alternate Webpage(s)	https://pubs.rsc.org/en/content/articlepdf/2018/sc/c8sc00428e
Alternate Webpage(s)	http://www.rsc.org/suppdata/c8/sc/c8sc00428e/c8sc00428e1.pdf
Alternate Webpage(s)	https://doi.org/10.1039/c8sc00428e
Journal	Chemical science
Language	English
Access Restriction	Open
Content Type	Text
Resource Type	Article