Interaction of electrons with cisplatin and the subsequent effect on DNA damage: a density functional theory study

Abstract

Cisplatin, Pt(NH₃)₂Cl₂, is a leading chemotherapeutic agent that has been widely used for various cancers. Recent experiments show that combining cisplatin and electron sources can dramatically enhance DNA damage and the cell-killing rate and, therefore, is a promising way to overcome the side effects and the resistance of cisplatin. However, the molecular mechanisms underlying this phenomenon are not clear yet. By using density functional theory calculations, we confirm that cisplatin can efficiently capture the prehydrated electrons and then undergo dissociation. The first electron attachment triggers a spontaneous departure of the chloride ion, forming a T-shaped [Pt(NH₃)₂Cl]˙ neutral radical, whereas the second electron attachment leads to a spontaneous departure of ammine, forming a linear [Pt(NH₃)Cl]⁻ anion. We further recognize that the one-electron reduced product [Pt(NH₃)₂Cl]˙ is extremely harmful to DNA. It can abstract hydrogen atoms from the C–H bonds of the ribose moiety and the methyl group of thymine, which in turn leads to DNA strand breaks and cross-link lesions. The activation energies of these hydrogen abstraction reactions are relatively small compared to the hydrolysis of cisplatin, a prerequisite step in the normal mechanism of action of cisplatin. These results rationalize the improved cytotoxicity of cisplatin by supplying electrons. Although the biological effects of the two-electron reduced product [Pt(NH₃)Cl]⁻ are not clear at this stage, our calculations indicate that it might be protonated by the surrounding water.