Platinum drugs and neurotoxicity: effects on intracellular calcium homeostasis

Abstract

[Pt(O,O'-acac)(γ-acac)(DMS)] (PtAcacDMS) is a new platinum compound showing low reactivity with nucleobases and specific reactivity with sulfur ligands intracellularly. It induces apoptosis in breast cancer cells, but appears to be less neurotoxic to the developing cerebellum than cisplatin (cisPt). The aim of this study was to assess the neurotoxicity of platinum compounds on calcium homeostasis in the dentate gyrus and Cornu Ammonis regions of the hippocampal formation during rat postnatal development. Two intracellular calcium homeostasis systems were taken for measurement, calbindin, a calcium buffer protein, and a plasma membrane calcium ATPase (PMCA1). The platinum compounds showed different effects on these markers in the two areas. One day after injection (PD11), cisPt decreased calbindin immunoreactivity and PMCA1 labeling in both regions; at PD17, the downregulation of PMCA1 persisted. Instead, PtAcacDMS produced varying effects on calbindin immunoreactivity in the two regions at PD11 and PD17; but in all cases, the changes incurred in calbindin immunoreactivity were counterbalanced by changes produced in PMCA1 expression. In conclusion, PtAcacDMS seems to affect calcium homeostasis in the central nervous system differently than cisPt. Both the platinum compounds act early to alter the calbindin buffering system. However, the most important difference between cisPt and PtAcacDMS is that, in vivo, the latter acts early to stimulate calcium efflux from nerve cells as reflected by its effect on PMCA1. The rapid onset of an activated calcium pump appears to be essential to cope with the excessive intracellular calcium concentration stemming from the downregulation of calbindin which could damage neuron function and morphology.