Oxaliplatin-Induced Peripheral Neuropathy via TRPA1 Stimulation in Mice Dorsal Root Ganglion Is Correlated with Aluminum Accumulation.
Oxaliplatin is a platinum-based anticancer drug used to treat metastatic colorectal, breast, and lung cancers. While oxaliplatin kills cancer cells effectively, it exhibits several side effects of varying severity. Neuropathic pain is commonly experienced during treatment with oxaliplatin. Patients describe symptoms of paresthesias or dysesthesias that are triggered by cold (acute neuropathy), or as abnormal sensory or motor function (chronic neuropathy). In particular, we found that aluminum levels were relatively high in some cancer patients suffering from neuropathic pain based on clinical observations. Based on these findings, we hypothesized that aluminum accumulation in the dorsal root ganglion (DRG) in the course of oxaliplatin treatment exacerbates neuropathic pain. In mice injected with oxaliplatin (three cycles of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest), we detected cold allodynia using the acetone test, but not heat hyperalgesia using a hot plate. However, co-treatment with aluminum chloride (AlCl3∙6H2O; 7 mg/kg i.p. for 14 days: equivalent 0.78 mg/kg of elemental Al) and oxaliplatin (1 cycle of 3 mg/kg i.p. daily for 5 days, followed by 5 days of rest) synergistically induced cold allodynia as well as increased TRPAl mRNA and protein expression. Inductively Coupled Plasma Mass Spectrometry (ICP-MS) analysis showed a significant increase in aluminum concentrations in the DRG of mice treated with aluminum chloride and oxaliplatin compared to aluminum chloride alone. Similarly, in a mouse induced-tumor model, aluminum concentrations were increased in DRG tissue and tumor cells after oxaliplatin treatment. Taken together, these findings suggest that aluminum accumulation in the DRG may exacerbate neuropathic pain in oxaliplatin-treated mice.
Institute of Cancer Research, College of Medicine, The Catholic University of Korea, Seoul, Korea.
Jin-Hee
JH
Park
Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
Jisook
J
Chae
Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
Kangsan
K
Roh
Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea; The Institute of Life Science and Technology, Sungkyunkwan University, Suwon, Korea.
Eui-Joon
EJ
Kil
Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
Minji
M
Lee
Department of Biological Science, Mokpo National University, Muan, Korea.
Chung-Kyun
CK
Auh
Department of Medical Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Korea.
Myung-Ah
MA
Lee
Yeom's Family Medicine Clinic, Seoul, Korea.
Chang-Hwan
CH
Yeom
Department of Genetic Engineering, Sungkyunkwan University, Suwon, Korea.
Sukchan
S
Lee
D000535:Aluminum / Q000378:metabolism*; D000818:Animals; D005727:Ganglia, Spinal / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000209:etiology*; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
D009944:Organoplatinum Compounds; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D000535:Aluminum