Several chemotherapy agents, particularly platinum drugs (oxaliplatin, cisplatin), taxanes (paclitaxel), and proteasome inhibitors (bortezomib), cause severe peripheral neurotoxicity, which is characterized by numbness and painful paresthesia in hands and feet. However, there is currently no effective strategy to prevent the side effects. Dimethyl fumarate (DMF) is a new oral drug that has been developed for the treatment of multiple sclerosis patients. DMF has neuroprotective effects via up-regulation of the nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent antioxidant response. In this study, we investigated the effect of DMF on chemotherapy agent-induced neurotoxicity in cultured cells and rat model.
Oxaliplatin (3 µM, 24h), cisplatin (10 µM, 24h), paclitaxel (10 nM, 24h), and bortezomib (300 nM, 24h) inhibited the neurite outgrowth in cultured PC12 cells and primary cultured rat dorsal root ganglion (DRG) neurons, respectively. We found that co-treatment of DMF (3, 10 µM, 24h) or its metabolite monomethyl fumarate (MMF; 3, 10 µM, 24h) attenuated oxaliplatin-, cisplatin- and bortezomib-induced inhibition of neurite outgrowth in PC12 and the cultured DRG neurons. On the other hand, neither DMF nor MMF attenuated paclitaxel-induced inhibition of both neurite outgrowth.
In rat model, repeated administration of oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) caused mechanical allodynia in von Frey test and axonal degeneration in sciatic nerve using toluidine blue staining. Co-treatment of DMF (200 mg/kg, p.o., five times per week for 4 weeks) relieved the oxaliplatin-induced mechanical allodynia and the axonal degeneration in sciatic nerve.
On the other hand, DMF (200 mg/kg, p.o., five times per week for 4 weeks) did not enhance the leukopenia, including neutropenia and lymphopenia, and the body weight loss induced by oxaliplatin (4 mg/kg, i.p., twice a week for 4 weeks) in rats. Furthermore, DMF and MMF did not also affect the anti-tumor effect of oxaliplatin in several cultured tumor cell lines (C26, mouse colon carcinoma; HCT116, human colon carcinoma; MKN45, human gastric adenocarcinoma; MIA PaCa-2, human pancreatic carcinoma).
These findings suggest that DMF has a potential protective action against chemotherapy-induced neurotoxicity, without affecting anti-tumor efficacy and the other side effects such as the pancytopenia and the body weight loss.
