Contributions of rat Ctr1 to the uptake and toxicity of copper and platinum anticancer drugs in dorsal root ganglion neurons.

نویسندگان

  • Johnson J Liu
  • Yaeseul Kim
  • Fang Yan
  • Qi Ding
  • Virginia Ip
  • Nancy N Jong
  • Julian F B Mercer
  • Mark J McKeage
چکیده

Dorsal root ganglion (DRG) neurons are affected by platinum-induced neurotoxicity and neurodegenerative processes associated with disturbed copper homeostasis and transport. This study aimed to understand the role of copper transporter 1 (Ctr1) in the uptake and toxicity of copper and platinum drugs in cultured rat DRG neurons, and the functional activities of rat Ctr1 (rCtr1) as a membrane transporter of copper and platinum drugs. Heterologous expression of rCtr1 in HEK293 cells (HEK/rCtr1 cells) increased the uptake and cytotoxicity of copper, oxaliplatin, cisplatin and carboplatin, in comparison to isogenic vector-transfected control cells. Cultured rat DRG neurons endogenously expressed rCtr1 protein on their neuronal cell body plasma membranes and cytoplasm, and displayed substantial capacity for taking up copper, but were resistant to copper toxicity. The uptake of copper by both cultured rat DRG neurons and HEK/rCtr1 cells was saturable and inhibited by cold temperature, silver and zinc, consistent with it being mediated by rCtr1. Cultured rat DRG neurons accumulated platinum during their exposure to oxaliplatin and were sensitive to oxaliplatin cytotoxicity. The accumulation of platinum by both cultured rat DRG neurons and HEK/rCtr1 cells, during oxaliplatin exposure, was saturable and temperature dependent, but was inhibited by copper only in HEK/rCtr1 cells. In conclusion, rCtr1 can transport copper and platinum drugs, and sensitizes cells to their cytotoxicities. DRG neurons display substantial capacity for accumulating copper via a transport process mediated by rCtr1, but appear able to resist copper toxicity and use alternative mechanisms to take up oxaliplatin.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Adrenomedullin protects rat dorsal root ganglion neurons against doxorubicin-induced toxicity by ameliorating oxidative stress

Objective(s): Despite effective anticancer effects, the use of doxorubicin (DOX) is hindered due to its cardio and neurotoxicity. The neuroprotective effect of adrenomedullin (AM) was shown in several studies. The present study aimed to evaluate the possible protective effects of AM against DOX-induced toxicity in dorsal root ganglia (DRGs) neurons. M...

متن کامل

Morphological Identification of Cell Death in Dorsal Root Ganglion Neurons Following Peripheral Nerve injury and repair in adult rat

Background: Axotomy causes sensory neuronal loss. Reconnection of proximal and distal nerve ends by surgical repair improves neuronal survival. It is important to know the morphology of primary sensory neurons after the surgical repair of their peripheral processes. Methods: Animals (male Wistar rats) were exposed to models of sciatic nerve transection, direct epineurial suture repair of sciati...

متن کامل

The Neuroprotective Effect of Nepeta menthoides on Axotomized Dorsal Root Ganglion Sensory Neurons in Neonate Rats

Background and Objective: Sensory neurons have critical role in improvement of functional outcome of any neuroprotective strategy. The herbal medicine Nepeta menthoides has been reported to have anti-apoptotic effect on axotomized spinal motoneurons. In the present study, the putative neuroprotective effect of Nepeta menthoides on the axotomized dorsal root ganglion sensory neurons in neonate r...

متن کامل

Differential expression of ATP7A, ATP7B and CTR1 in adult rat dorsal root ganglion tissue

BACKGROUND ATP7A, ATP7B and CTR1 are metal transporting proteins that control the cellular disposition of copper and platinum drugs, but their expression in dorsal root ganglion (DRG) tissue and their role in platinum-induced neurotoxicity are unknown. To investigate the DRG expression of ATP7A, ATP7B and CTR1, lumbar DRG and reference tissues were collected for real time quantitative PCR, RT-P...

متن کامل

Oxaliplatin transport mediated by organic cation/carnitine transporters OCTN1 and OCTN2 in overexpressing human embryonic kidney 293 cells and rat dorsal root ganglion neurons.

The organic cation/carnitine transporters OCTN1 and OCTN2 are related to other organic cation transporters (OCT1, OCT2, and OCT3) known for transporting oxaliplatin, an anticancer drug with dose-limiting neurotoxicity. In this study, we sought to determine whether OCTN1 and OCTN2 also transported oxaliplatin and to characterize their functional expression and contributions to its neuronal accum...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:
  • Biochemical pharmacology

دوره 85 2  شماره 

صفحات  -

تاریخ انتشار 2013