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

Liu, JJ; Kim, Yaeseul; Yan, Fang; Ding, Qi; Ip, Virginia; Jong, Nancy N.; Mercer, Julian F. B.; McKeage, Mark J.

doi:10.1016/j.bcp.2012.10.023

Cited by 36 publications

(34 citation statements)

References 52 publications

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“…It is difficult to estimate the concentration of oxaliplatin that sensory neurons are exposed to in human patients. While the plasma concentration of free oxaliplatin after intravenous administration is relatively low [18; 22], consistent with an apparent large volume of distribution, oxaliplatin is likely to accumulate in sensory neurons through active transport by copper transporters and the L-carnitine transporter OCTN1 [25; 30]. …”

Section: Discussionmentioning

confidence: 99%

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Deuis

Zimmermann

Romanovsky

et al. 2013

Pain

151

194

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Cold allodynia, pain in response to cooling, occurs during or within hours of oxaliplatin infusion and is thought to arise from a direct effect of oxaliplatin on peripheral sensory neurons. To characterize the pathophysiological mechanisms underlying acute oxaliplatin-induced cold allodynia, we established a new intraplantar oxaliplatin mouse model that rapidly developed long-lasting cold allodynia mediated entirely through tetrodotoxin-sensitive Nav pathways. Using selective inhibitors and knockout animals, we found that Nav1.6 was the key isoform involved, while thermosensitive transient receptor potential channels were not involved. Consistent with a crucial role for delayed-rectifier potassium channels in excitability in response to cold, intraplantar administration of the K+-channel blocker 4-aminopyridine mimicked oxaliplatin-induced cold allodynia and was also inhibited by Navl.6 blockers. Intraplantar injection of the Nav1.6-activator Cn2 elicited spontaneous pain, mechanical allodynia and enhanced 4-aminopyridine-induced cold allodynia. These findings provide behavioural evidence for a crucial role of Nav1.6 in multiple peripheral pain pathways including cold allodynia.

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Section: Discussionmentioning

confidence: 99%

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Deuis

Zimmermann

Romanovsky

et al. 2013

Pain

151

194

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“…; Liu et al . ). In brief, DRG from all spinal levels were dissected from 20‐day‐old Wistar rats killed with pentobarbitone (Chemstock Animal Health, Christchurch, New Zealand).…”

Section: Methodsmentioning

confidence: 97%

Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Yan

Liu

et al. 2015

Journal of Neurochemistry

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Platinum-based anticancer drugs cause peripheral neurotoxicity by damaging sensory neurons within the dorsal root ganglia (DRG), but the mechanisms are incompletely understood. The roles of platinum DNA binding, transcription inhibition and altered cell size were investigated in primary cultures of rat DRG cells. Click chemistry quantitative fluorescence imaging of RNAincorporated 5-ethynyluridine showed high, but wide ranging, global levels of transcription in individual neurons that correlated with their cell body size. Treatment with platinum drugs reduced neuronal transcription and cell body size to an extent that corresponded to the amount of preceding platinum DNA binding, but without any loss of neuronal cells. The effects of platinum drugs on neuronal transcription and cell body size were inhibited by blocking platinum DNA binding with sodium thiosulfate, and mimicked by treatment with a model transcriptional inhibitor, actinomycin D. In vivo oxaliplatin treatment depleted the total RNA content of DRG tissue concurrently with altering DRG neuronal size. These findings point to a mechanism of chemotherapy-induced peripheral neurotoxicity, whereby platinum DNA damage induces global transcriptional arrest leading in turn to neuronal atrophy. DRG neurons may be particularly vulnerable to this mechanism of toxicity because of their requirements for high basal levels of global transcriptional activity. Keywords: anticancer drug toxicity, DNA damage, DRG neurons, global transcription, neuronal atrophy, neurotoxicity. The platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, are used clinically for the routine treatment of a wide range of human cancers. Their mechanism of action involves platinum binding to DNA at the N7 position of purine bases to form bifunctional 1,2-and 1,3-intrastrand crosslinks on the DNA template, which inhibit DNA replication and transcription, leading to tumour cell cycle arrest and apoptosis (Wang and Lippard 2005). Platinum drugs also cause peripheral neurotoxicity by damaging postmitotic dorsal root ganglia (DRG) sensory neurons (Avan et al. 2015). In the clinic, the resulting neurological symptoms and functional deficits can interfere with the delivery of cancer chemotherapy or persist long after completion of treatment, thereby compromising patient quality of life and the chance of cancer control or cure. Abbreviations used: AUC, area under the concentration-time curve; DACH, diaminocyclohexane; DNA-PK, DNA-dependent protein kinase; DRG, dorsal root ganglia; EU, 5-ethynyluridine; IQR, interquartile range; PARP-1, poly(ADP-ribose) polymerase 1; TUNEL, terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling.

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“…An important contributing factor to the development of CIPN is thought to be the cellular uptake and accumulation of platinum-derivatives in sensory neurons (Liu et al, 2009, 2012, 2013). Specifically, the copper transporter 1 (CTR1), members of the organic cationic transporter family (OCT), and copper-transporting ATPases have been proposed as key transporters maintaining the intracellular concentration of platinum derivatives via active uptake and efflux processes (Holzer et al, 2006; Liu et al, 2012; Sprowl et al, 2013; Cavaletti et al, 2014).…”

Section: The Genetics Of Chemotherapy-induced Peripheral Neuropathymentioning

confidence: 99%

“…Several of these transporters are also expressed on the plasma membrane of dorsal root ganglion cells, where they presumably contribute to the development of CIPN. While the human CTR1 plays a particularly important role in both resistance to platinum drugs and uptake in sensory neurons in vivo and in vitro (Song et al, 2004; Liu et al, 2009, 2013), residual oxaliplatin accumulation in murine embryonic fibroblast from CTR1 −/− animals suggests the existence of additional transport mechanisms leading to accumulation of platinum-based compounds (Holzer et al, 2006). These likely include the organic cationic transporters belonging to the solute carrier family.…”

Section: The Genetics Of Chemotherapy-induced Peripheral Neuropathymentioning

confidence: 99%

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

Starobova

Vetter

2017

Front. Mol. Neurosci.

472

400

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Chemotherapy-induced neuropathy is a common, dose-dependent adverse effect of several antineoplastics. It can lead to detrimental dose reductions and discontinuation of treatment, and severely affects the quality of life of cancer survivors. Clinically, chemotherapy-induced peripheral neuropathy presents as deficits in sensory, motor, and autonomic function which develop in a glove and stocking distribution due to preferential effects on longer axons. The pathophysiological processes are multi-factorial and involve oxidative stress, apoptotic mechanisms, altered calcium homeostasis, axon degeneration and membrane remodeling as well as immune processes and neuroinflammation. This review focusses on the commonly used antineoplastic substances oxaliplatin, cisplatin, vincristine, docetaxel, and paclitaxel which interfere with the cancer cell cycle—leading to cell death and tumor degradation—and cause severe acute and chronic peripheral neuropathies. We discuss drug mechanism of action and pharmacokinetic disposition relevant to the development of peripheral neuropathy, the epidemiology and clinical presentation of chemotherapy-induced neuropathy, emerging insight into genetic susceptibilities as well as current understanding of the pathophysiology and treatment approaches.

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

Cited by 36 publications

References 52 publications

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

An animal model of oxaliplatin-induced cold allodynia reveals a crucial role for Nav1.6 in peripheral pain pathways

Role of platinum DNA damage‐induced transcriptional inhibition in chemotherapy‐induced neuronal atrophy and peripheral neurotoxicity

Pathophysiology of Chemotherapy-Induced Peripheral Neuropathy

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