%0 Journal Article
%T Electron Microscopy in Rat Brain Slices Reveals Rapid Accumulation of Cisplatin on Ribosomes and Other Cellular Components Only in Glia
%A Lidia Zueva
%A Yomarie Rivera
%A Lilia Kucheryavykh
%A Serguei N. Skatchkov
%A Misty J. Eaton
%A Priscila Sanabria
%A Mikhail Inyushin
%J Chemotherapy Research and Practice
%D 2014
%I Hindawi Publishing Corporation
%R 10.1155/2014/174039
%X Cisplatin is a widely used, effective anticancer drug. Its use, however, is associated with several side effects including nephrotoxicity and neurotoxicity. It is known that cisplatin is accumulated in cells by the organic cation transport system and reacts with nucleotides, damaging them, but the precise target of cisplatin-induced neurotoxicity remains obscure. Here we report direct visualization of cisplatin inside brain cells using in vivo ¡°cisplatin staining,¡± a technique that takes advantage of the high electron density of cisplatin, which contains platinum (). After applying 0.1% cisplatin to living brain slices for 30£¿min, we fixed the tissue and observed the accumulated cisplatin using electron microscopy. We found that cisplatin was localized mainly to ribosomes associated with endoplasmic reticulum (EPR) in glial cells and to the myelin sheath formed by oligodendrocytes around neuronal axons. Staining of nuclear DNA was moderate. Our in vivo ¡°cisplatin staining¡± method validated that the main target of cisplatin is a direct attack on myelin and the RNA contained in ribosomes. 1. Introduction Cisplatin (cis-diamminedichloroplatinum) (other names¡ªPlatinol AQ or Platinol) is an effective anticancer drug and one of the most commonly used chemotherapies in the USA [1]. It is transported into cancerous cells by organic cation transporters (OCTs and OCTNs; [SLC22A1¨C5]) [2, 3] leading to intracellular accumulation of cisplatin. The presence of OCTs was confirmed in different cancer cell lines [4, 5]. Moreover, we previously reported effective uptake of OCT substrates by glioma cells [6]. It is likely that specific uptake of cisplatin is associated with the same transport mechanism. OCTs are present in different normal tissues as well; the most well-defined examples are tubular epithelium cells in kidney [7] and astrocytes, pericytes, and oligodendrocytes in the nervous system [8, 9]. This may be the reason why cisplatin treatment is associated with numerous side effects such as nephrotoxicity and neurotoxicity [10]. While there are methods to reduce kidney damage, neurotoxicity remains a major dose-limiting factor for cisplatin therapy [11]. Patients with cisplatin-induced peripheral neuropathy typically present distal sensory ataxia, degeneration of large myelinated axons with signs of segmental demyelination and remyelination [12]. The histologic approach revealed that large axons are more frequently affected than the small ones, and nonmyelinated axons are unaffected [13]. Motor fibers are usually unaffected and overall damage to cells protected
%U http://www.hindawi.com/journals/cherp/2014/174039/