Possible Interaction: Cisplatin and Copper

“Appreciation of the role of the Cu transporters in the development of resistance to DDP , CBDCA, and L-OHP offers novel insights into strategies for preventing or reversing resistance to this very important family of anticancer drugs.”

“Molecular modeling predicts 3 Cu and cDDP binding sites and quantum chemistry calculations indicate that cDDP would be expected to displace Cu from each of these sites.”

“ cDDP was found to bind MEK1/2 in whole cells and the extent of binding was augmented by supplementary Cu and reduced by Cu chelation.”

“These results … concentration of copper causes a significant … accumulation of CDDP and binding of platinum to DNA independently of CTR1 expression in KB cells and CDDP-resistant sublines thereof and … of CDDP resistance is associated with a greatly reduced level of ATP7A and a marginally lower expression of CTR1.”

“ConclusionsIn this model system, cross-resistance between Cu and DDP was bidirectional and accompanied by parallel changes in the cellular pharmacokinetics of both compounds.”

“ Cu reduced the accumulation of DDP in the HuH7 cells in a concentration-dependent manner and vice versa.”

“ DDP also reduced the efflux of Cu.”

“ Copper and DDP each inhibited the ATP-dependent transport of the other.”

“ cis-DDP significantly reduced cellular Zn (20%) and Cu (23%) levels particularly in the kidneys.”

“A protective effect of preadministration of the metals Cu , Bi, Zn, Hg, Cd, Ni or Co, against lethal toxicity of cis-diamminedichloroplatinum (Cisplatin; CDDP) was observed in mice.”

“ Cisplatin also produced a small increase in the concentration of Cu in the brain but had no significant effect on total Cu and Zn concentrations in the heart, thymus, liver, intestine, spleen, testes and muscle.”

“The administration of cisplatin to the Cd2+-pretreated rat decreased the content of metallothionein-bound Cu in parallel with a reduction in total renal Cu content, but had no significant effect on the total renal content of Cd and Zn.”

“increased the renal Cu content whilst cisplatin pretreatment inhibited the uptake of Cu by the kidneys.”

“In mice subcutaneously inoculated with Ehrlich tumor cells, the preadministration of copper also depressed the lethal and renal toxicity of CDDP without compromising its antitumor activity.”

“ Cisplatin treatment reduces the concentration of Cu and Zn in the renal metallothionein and other soluble protein fractions in the kidney.”