Abstract 4389: Copper and platinum uptake in cultured rat dorsal root ganglion neurons

Abstract

Abstract Peripheral neuropathy is a dose-limiting toxicity of platinum drugs due to their accumulation in the dorsal root ganglia (DRG) and damage to sensory neurons. Our previous studies showed a specific pattern of expression of copper transporters in rat DRG tissue (Liu JJ et al 2009; Ip V et al 2010). Here we aimed to investigate their functional activity in the uptake of copper and platinum in cultured DRG neurons in vitro. Dissociated rat DRG neurons were cultured in N2-supplemented Neurobasal-A medium. Cellular metal levels were measured by the inductively coupled plasma mass spectrometry. The copper content of the cultured DRG neurons increased linearly with time (R2, 0.7952 ∼ 0.8903) during a one hour exposure to 3 ∼ 100 µM of CuCl2. The rate of cellular uptake of copper had nonlinear dependence (R2, 0.9629) on the exposure concentration of CuCl2, with a maximal uptake rate of 0.237 ± 0.041 nmole/min/mg protein and CuCl2 concentration achieving half-maximal uptake of 49.1 µM. The uptake of copper was temperature-dependent, stimulated by ascorbate and inhibited by zinc. CTR1 mRNA was detectable in cultured DRG neurons and its protein co-localised with microtubule-associated protein 2-positive neuronal cell bodies. Oxaliplatin inhibited copper uptake by DRG neurons and their platinum content increased linearly with time (R2, 0.916) during a one hour oxaliplatin exposure. In conclusion, CTR1 is functionally expressed by rat DRG neurons in primary culture. Oxaliplatin accumulates and inhibits copper uptake in DRG neurons. Supported by research grants from Cancer Society of New Zealand and McBeath Child Cancer Trust Fund. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4389. doi:10.1158/1538-7445.AM2011-4389