Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy

Shunsuke Fujita, Takeshi Hirota, Ryo Sakiyama, Misaki Baba, Ichiro Ieiri

研究成果: ジャーナルへの寄稿記事

2 引用 (Scopus)

抄録

Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy. (Figure presented.).

元の言語英語
ページ(範囲)373-385
ページ数13
ジャーナルJournal of Neurochemistry
148
発行部数3
DOI
出版物ステータス出版済み - 2 1 2019

Fingerprint

oxaliplatin
Peripheral Nervous System Diseases
Spinal Ganglia
Platinum
Pharmaceutical Preparations
Small Interfering RNA
Rats
Rat control
Mass spectrometers
Tumors
Real-Time Polymerase Chain Reaction
Colorectal Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cellular and Molecular Neuroscience

これを引用

Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy. / Fujita, Shunsuke; Hirota, Takeshi; Sakiyama, Ryo; Baba, Misaki; Ieiri, Ichiro.

:: Journal of Neurochemistry, 巻 148, 番号 3, 01.02.2019, p. 373-385.

研究成果: ジャーナルへの寄稿記事

@article{33f0eb41a6724533baa51299fe9984c3,
title = "Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy",
abstract = "Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy. (Figure presented.).",
author = "Shunsuke Fujita and Takeshi Hirota and Ryo Sakiyama and Misaki Baba and Ichiro Ieiri",
year = "2019",
month = "2",
day = "1",
doi = "10.1111/jnc.14607",
language = "English",
volume = "148",
pages = "373--385",
journal = "Journal of Neurochemistry",
issn = "0022-3042",
publisher = "Wiley-Blackwell",
number = "3",

}

TY - JOUR

T1 - Identification of drug transporters contributing to oxaliplatin-induced peripheral neuropathy

AU - Fujita, Shunsuke

AU - Hirota, Takeshi

AU - Sakiyama, Ryo

AU - Baba, Misaki

AU - Ieiri, Ichiro

PY - 2019/2/1

Y1 - 2019/2/1

N2 - Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy. (Figure presented.).

AB - Oxaliplatin is widely used as a key drug in the treatment of colorectal cancer. However, its administration is associated with the dose-limiting adverse effect, peripheral neuropathy. Platinum accumulation in the dorsal root ganglion (DRG) is the major mechanism responsible for oxaliplatin-induced neuropathy. Some drug transporters have been identified as platinum complex transporters in kidney or tumor cells, but not yet in DRG. In the present study, we investigated oxaliplatin transporters and their contribution to peripheral neuropathy. We identified 12 platinum transporters expressed in DRG with real-time PCR, and their transiently overexpressing cells were established. After exposure to oxaliplatin, the accumulation of platinum in these overexpressing cells was evaluated using a coupled plasma mass spectrometer. Octn1/2- and Mate1-expressing cells showed the intracellular accumulation of oxaliplatin. In an animal study, peripheral neuropathy developed after the administration of oxaliplatin (4 mg/kg, intravenously, twice a week) to siRNA-injected rats (0.5 nmol, intrathecally, once a week) was demonstrated with the von Frey test. The knockdown of Octn1 in DRG ameliorated peripheral neuropathy, and decreased platinum accumulation in DRG, whereas the knockdown of Octn2 did not. Mate1 siRNA-injected rats developed more severe neuropathy than control rats. These results indicate that Octn1 and Mate1 are involved in platinum accumulation at DRG and oxaliplatin-induced peripheral neuropathy. (Figure presented.).

UR - http://www.scopus.com/inward/record.url?scp=85058023617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058023617&partnerID=8YFLogxK

U2 - 10.1111/jnc.14607

DO - 10.1111/jnc.14607

M3 - Article

VL - 148

SP - 373

EP - 385

JO - Journal of Neurochemistry

JF - Journal of Neurochemistry

SN - 0022-3042

IS - 3

ER -