Title
Revisiting [PtCl2(cis-1,4-DACH)]: an underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer
Document Type
Article
Publication Date
2012
Department/School
Chemistry
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.
Link to Published Version
Recommended Citation
Margiotta, N., Marzano, C., Gandin, V., Osella, D., Ravera, M., Gabano, E., … Natile, G. (2012). Revisiting [PtCl2(cis-1,4-DACH)]: An underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer. Journal of Medicinal Chemistry, 55(16), 7182–7192. doi:10.1021/jm3006838