Dimethyl Fumarate Attenuates Oxaliplatin-Induced Peripheral Neuropathy without Affecting the Anti-tumor Activity of Oxaliplatin in Rodents

• Published in: Biological & pharmaceutical bulletin Vol. 42; no. 4; pp. 638 - 644
• Main Authors: Miyagi, Anna, Kawashiri, Takehiro, Shimizu, Shiori, Shigematsu, Nao, Kobayashi, Daisuke, Shimazoe, Takao
• Format: Journal Article
• Language: English
• Published: Japan The Pharmaceutical Society of Japan 01-04-2019; Pharmaceutical Society of Japan; Japan Science and Technology Agency
• Subjects: Acetone; Adenocarcinoma; Animals; Antineoplastic Agents; Antitumor agents; axonal degeneration; Body weight; Body weight loss; Bone marrow; Cell Line, Tumor; Colon; Dimethyl; dimethyl fumarate; Dimethyl Fumarate - pharmacology; Dimethyl Fumarate - therapeutic use; Erythrocytes; Hyperalgesia - chemically induced; Hyperalgesia - drug therapy; Leukocytes (neutrophilic); Lymphocytes; Male; mechanical allodynia; Mice, Inbred BALB C; Multiple sclerosis; Myelosuppression; Neoplasms - drug therapy; Neoplasms - pathology; Neurodegeneration; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oral administration; Oxaliplatin; Oxidative stress; Pain perception; Pancreatic cancer; Pancreatic carcinoma; Peripheral Nervous System Diseases - chemically induced; Peripheral Nervous System Diseases - drug therapy; Peripheral neuropathy; Rats, Sprague-Dawley; Rodents; Sciatic nerve; Sciatic Nerve - drug effects; Sciatic Nerve - pathology; Side effects; Tumor Burden - drug effects; Weight loss; oxaliplatin; axonal degeneration; dimethyl fumarate; mechanical allodynia; peripheral neuropathy
• ISSN: 0918-6158; 1347-5215
• DOI: 10.1248/bpb.b18-00855

Oxaliplatin has been used as a first choice for colorectal, gastric and pancreatic cancer, but it induces peripheral neuropathies. Dimethyl fumarate (DMF) is an oral drug for multiple sclerosis with neuroprotective effects on oxidative stress. Using both in vivo and in vitro models, we investigated the effects of DMF on oxaliplatin-induced peripheral neuropathy and other side effects, as well as on the anti-tumor activity of oxaliplatin. Repeated intraperitoneal injection of 4 mg/kg oxaliplatin (twice per week for 4 weeks) caused mechanical allodynia (as revealed by the von Frey tests), cold hyperalgesia (as revealed by the acetone tests), and axonal degeneration in the sciatic nerve of rats. Co-administration of oral DMF (200 mg/kg, five times per week for 4 weeks) relieved oxaliplatin-induced mechanical allodynia but not cold hyperalgesia, and ameliorated axonal degeneration. In addition, DMF did not exacerbate oxaliplatin-induced body weight loss or bone marrow suppression, such as reduction in red blood cells, white blood cells, neutrophils and lymphocytes. Furthermore, DMF did not inhibit the anti-tumor activity of oxaliplatin in any cultured cancer cell line (C26, mouse colon carcinoma; HCT116, human colon carcinoma; MKN45, human gastric adenocarcinoma; MIA PaCa-2, human pancreatic carcinoma) or C26-bearing mice. These results suggest that DMF prevents oxaliplatin-induced mechanical allodynia and axonal degeneration without affecting the anti-tumor activity of oxaliplatin. Therefore, DMF may be useful for managing oxaliplatin-induced chronic peripheral neuropathy.