Taxanes and platinum derivatives impair Schwann cells via distinct mechanisms.

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.

• Authors: Satoshi Imai, Madoka Koyanagi, Ziauddin Azimi, Yui Nakazato, Mayuna Matsumoto, Takashi Ogihara, Atsushi Yonezawa, Tomohiro Omura, Shunsaku Nakagawa, Shuji Wakatsuki, Toshiyuki Araki, Shuji Kaneko, Takayuki Nakagawa, Kazuo Matsubara
• Journal: Scientific reports (Sci Rep) Vol. 7 Issue 1 Pg. 5947 (07 20 2017) ISSN: 2045-2322 [Electronic] England
• PMID: 28729624 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Galectin 3
• Receptor, Nerve Growth Factor
• Taxoids
• Oxaliplatin
• Platinum
• Paclitaxel
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Cell Dedifferentiation (drug effects)
• Cell Shape (drug effects)
• Cell Survival (drug effects)
• Cells, Cultured
• Cisplatin (pharmacology)
• Coculture Techniques
• Galectin 3 (metabolism)
• Ganglia, Spinal (drug effects, metabolism)
• Mice
• Mitochondria (drug effects, metabolism)
• Myelin Sheath (metabolism)
• Neurons (drug effects, metabolism)
• Oxaliplatin (pharmacology)
• Paclitaxel (pharmacology)
• Platinum (pharmacology)
• Rats
• Receptor, Nerve Growth Factor (metabolism)
• Schwann Cells (drug effects, metabolism, pathology)
• Sciatic Nerve (cytology, drug effects, metabolism)
• Taxoids (pharmacology)