Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms

Satoshi Imai,Shuji Wakatsuki,Takashi Ogihara,Atsushi Yonezawa,Yui Nakazato,Mayuna Matsumoto,Shuji Kaneko,Shunsaku Nakagawa,Kazuo Matsubara,Ziauddin Azimi,Madoka Koyanagi,Takayuki Nakagawa,Tomohiro Omura,Toshiyuki Araki

doi:10.1038/s41598-017-05784-1

Abstract

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), however, the precise underlying mechanisms are not fully understood. Here, we examined the direct effects of anti-cancer agents on Schwann cells. Exposure of primary cultured rat Schwann cells to paclitaxel (0.01 μM), cisplatin (1 μM), or oxaliplatin (3 μM) for 48 h induced cytotoxicity and reduced myelin basic protein expression at concentrations lower than those required to induce neurotoxicity in cultured rat dorsal root ganglion (DRG) neurons. Similarly, these anti-cancer drugs 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 Schwann cells into an immature state, characterized by increased expression of p75 and galectin-3. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve. These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons.

Highlights

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), the precise underlying mechanisms are not fully understood
We show for the first time that treatment with paclitaxel induces the dedifferentiation of myelin-forming Schwann cells, whereas cisplatin and oxaliplatin induced cytotoxicity accompanied by mitochondrial dysfunction at concentrations lower than those required to impairment of dorsal root ganglion (DRG) neurons
To gain further insight into the direct effects of anti-cancer agents on Schwann cells, we examined the effects of paclitaxel, cisplatin and oxaliplatin on the morphology of differentiated Schwann cells (Fig. 3a)

Summary

Introduction

Impairment of peripheral neurons by anti-cancer agents, including taxanes and platinum derivatives, has been considered to be a major cause of chemotherapy-induced peripheral neuropathy (CIPN), the precise underlying mechanisms are not fully understood. Consistent with in vitro findings, repeated injection of paclitaxel increased expression of p75 and galectin-3 in Schwann cells within the mouse sciatic nerve These results suggest that taxanes and platinum derivatives impair Schwan cells by inducing dedifferentiation and mitochondrial dysfunction, respectively, which may be important in the development of CIPN in conjunction with their direct impairment in peripheral neurons. Schwann cells play a major supportive role in the maintenance of the peripheral nervous system, raising the intriguing possibility that impairment of Schwann cells and consequent disruption of intercellular interactions between myelin-forming mature Schwann cells and axons by anti-cancer agents may be important for the pathogenesis of CIPN Based on this hypothesis, the present study was designed to ascertain the direct effect of anti-cancer agents (paclitaxel, cisplatin and oxaliplatin) on primary Schwann cell cultures and on myelin-forming Schwann cells in the mouse sciatic nerve

Methods

Results

Conclusion