Direct impairment of Schwann cells by taxanes and platinum derivatives participates in the chemotherapy-induced peripheral neuropathy pathogenesis

[Speaker] Madoka Koyanagi:1
[Co-author] Satoshi Imai:1, Mayuna Matsumoto:1, Takashi Ogihara:1, Yui Nakazato:1, Takayuki Nakagawa:1, Kazuo Matsubara:1
1:Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Japan

BACKGROUND: Chemotherapeutic agents such as taxanes and platinum derivatives frequently induce chemotherapy-induced peripheral neuropathy (CIPN). It has been considered that the direct impairment of peripheral sensory neurons should be a major cause of CIPN, however, the precise underlying mechanisms are not fully understood. To address this issue, we focused on major supportive roles of Schwann cells in the maintenance of peripheral nervous systems, and examined the direct effects of anti-cancer agents on these cells.
METHODS: We evaluated the direct effect of anti-cancer agents (paclitaxel, cisplatin and oxaliplatin) on primary cultured Schwann cells obtained from sciatic nerves of Wistar/ST rat pups (post-natal days 1-4). Cell viabilities were measured by MTT assay. Rat primary cultured dorsal root ganglia (DRG) neurons from adult male rats (6-8 weeks old) and Schwann cell/DRG neuron co-cultures were also exposed to each anti-cancer drug. Morphological changes in each culture system were detected by immunocytochemistry. Expressions of Schwann cell markers were evaluated by immunocytochemical analysis, western blotting or real-time PCR assay. Mitochondrial activities were analyzed using MitoTracker®. Paclitaxel (4 mg/kg x 4) was repeatedly injected intraperitoneally into male C57BL/6J mice (6 weeks old).
RESULTS: Exposure of paclitaxel (0.01 μM), cisplatin (1 μM) or oxaliplatin (3 μM) for 48 h to primary cultured Schwann cells induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured DRG neurons. Similarly, these anti-cancer agents disrupted myelin formation in Schwann cell/DRG neuron co-cultures without affecting nerve axons. Cisplatin and oxaliplatin, but not paclitaxel, caused mitochondrial dysfunction in cultured Schwann cells. By contrast, paclitaxel led to dedifferentiation of mature Schwann cells into the immature state, characterized by increased-expression of immature and dedifferentiated Schwann cells markers, p75 and galectin-3, respectively. Consistent with in vitro findings, repeated administration of paclitaxel elevated expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerves.
CONCLUSIONS: These results suggest that taxanes and platinum derivatives directly impair Schwann cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, thereby triggering the pathogenic mechanisms underlying CIPN in conjunction with their direct impairment in peripheral neurons.

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