Revisiting [PtCl₂(cis-1,4-DACH)]: an underestimated antitumor drug with potential application to the treatment of oxaliplatin-refractory colorectal cancer.
Although the encouraging antitumor activity of [PtCl(2)(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.
Dipartimento Farmaco-Chimico, Università di Bari "A. Moro", via E. Orabona 4, 70125 Bari, Italy. nicola.margiotta@uniba.it
Nicola
N
Margiotta
Cristina
C
Marzano
Valentina
V
Gandin
Domenico
D
Osella
Mauro
M
Ravera
Elisabetta
E
Gabano
James A
JA
Platts
Emanuele
E
Petruzzella
James D
JD
Hoeschele
Giovanni
G
Natile
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D015374:Biosensing Techniques; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy; D045744:Cell Line, Tumor / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000188:drug therapy*; D004247:DNA / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D019384:Nucleic Acid Synthesis Inhibitors; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology* / Q000627:therapeutic use; D000077150:Oxaliplatin; D011789:Quantum Theory
D000970:Antineoplastic Agents; D018736:DNA Adducts; D019384:Nucleic Acid Synthesis Inhibitors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D002945:Cisplatin