Revisiting [PtCl2(cis-1,4-DACH)]: An underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer

Nicola Margiotta, Cristina Marzano, Valentina Gandin, Domenico Osella, Mauro Ravera, Elisabetta Gabano, James A. Platts, Emanuele Petruzzella, James D. Hoeschele, Giovanni Natile

Risultato della ricerca: Contributo su rivistaArticolo in rivistapeer review

Abstract

Although the encouraging antitumor activity of [PtCl2(cis-1,4- DACH)] (1; DACH = diaminocyclohexane) was shown in early studies almost 20 years ago, the compound has remained nearly neglected. In contrast, oxaliplatin, containing the isomeric 1(R),2(R)-DACH carrier ligand, enjoys worldwide clinic application as a most important therapeutic agent in the treatment of colorectal cancer. By extending the investigation to human chemotherapy-resistant cancer cells, we have demonstrated the real effectiveness of 1 in circumventing cisplatin and oxaliplatin resistance in LoVo colon cancer cells. The uptake of compound 1 by the latter cells was similar to that of sensitive LoVo cells. This is not the case for all other compounds considered in this investigation. Interaction with double-stranded DNA, investigated by a biosensor assay and by quantum mechanical/molecular mechanical geometry optimization of the 1,2-GG intrastrand cross-link, does not show significant differences between 1 and oxaliplatin. However, the DNA adducts of 1 are removed from repair systems with lower efficiency and are more effective in inhibiting DNA and RNA polymerase.

Lingua originaleInglese
pagine (da-a)7182-7192
Numero di pagine11
RivistaJournal of Medicinal Chemistry
Volume55
Numero di pubblicazione16
DOI
Stato di pubblicazionePubblicato - 23 ago 2012

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