Dinuclear Alkylamine Platinum(<scp>II</scp>) Complexes of [1,2‐Bis(4‐fluorophenyl)ethylenediamine]platinum(<scp>II</scp>): Influence of Endocytosis and Copper and Organic Cation Transport Systems on Cellular Uptake

Abstract

Various possible pathways for the uptake of cationic alkylamine platinum(II) complexes into the MCF-7 breast cancer cells were studied with di[meso-1,2-bis(4-fluorophenyl)ethylenediamine]di[sulfinylbis(methane)-S][mu-1,6-diaminohexaneN:N']diplatinum(II) disulfate (m-4F-PtDMSO-DAH) as an example. It was demonstrated that m-4F-PtDMSO-DAH competed neither for the copper transporter nor the organic cation transporters (OCT and OATP). Instead, adsorptive endocytosis by macropinocytosis played an essential role. Inhibitors of this processes such as amiloride, N-ethyl-N-isopropylamiloride (EIPA), wortmannin, and cytochalasin D decreased the intracellular uptake of m-4F-PtDMSO-DAH dramatically. These results support the understanding of the pharmacological behavior of this promising drug family, which showed no cross resistance with cisplatin.