TY - JOUR
T1 - Revisiting [PtCl2(cis-1,4-DACH)]
T2 - An underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer
AU - Margiotta, Nicola
AU - Marzano, Cristina
AU - Gandin, Valentina
AU - Osella, Domenico
AU - Ravera, Mauro
AU - Gabano, Elisabetta
AU - Platts, James A.
AU - Petruzzella, Emanuele
AU - Hoeschele, James D.
AU - Natile, Giovanni
PY - 2012/8/23
Y1 - 2012/8/23
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866889209&partnerID=8YFLogxK
U2 - 10.1021/jm3006838
DO - 10.1021/jm3006838
M3 - Article
SN - 0022-2623
VL - 55
SP - 7182
EP - 7192
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 16
ER -