Delayed treatment with vitamin C and N-acetyl-l-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib
Delayed treatment with vitamin C and N-acetyl-l-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib
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DOI：
10.1007/s12185-011-0850-7
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发表时间：
2011-04
影响因子：
2.1
通讯作者：
A. Nakano;M. Abe;Asuka Oda;Hiroe Amou;M. Hiasa;S. Nakamura;H. Miki;T. Harada;S. Fujii;K. Kagawa;K. Takeuchi;Takashi Watanabe;S. Ozaki;Toshio Matsumoto
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文献类型：
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作者：
A. Nakano;M. Abe;Asuka Oda;Hiroe Amou;M. Hiasa;S. Nakamura;H. Miki;T. Harada;S. Fujii;K. Kagawa;K. Takeuchi;Takashi Watanabe;S. Ozaki;Toshio Matsumoto
硼替佐米诱导的周围神经病变（BIPN）是一种致残性不良反应。由于BIPN的大鼠模型已证明神经雪旺细胞受损，我们筛选了细胞保护剂，以设计一种方法，在不影响其抗骨髓瘤作用的情况下，从硼替佐米的细胞毒性作用中拯救雪旺细胞。雪旺细胞经历了大自噬沿着胞质包涵体和空泡形成，并且似乎比骨髓瘤细胞对硼替佐米诱导的细胞毒性更不敏感。维生素C或N-乙酰基-L-半胱氨酸（NAC）实现了用30 nM或更低剂量硼替佐米处理的许旺细胞的几乎完全拯救，并且这些药剂组合能够协同抑制具有较高剂量硼替佐米的许旺细胞中的形态学变化和细胞毒性。暴露于硼替佐米后延迟添加维生素C和/或NAC减轻了雪旺细胞的细胞毒性，但对骨髓瘤细胞无影响。这些结果表明，延迟治疗这些药物可能有助于预防BIPN。
Bortezomib-induced peripheral neuropathy (BIPN) emerges as a disabling adverse effect. As rat models for BIPN have demonstrated damage in nerve Schwann cells, we screened for cytoprotective agents to devise a method of rescuing Schwann cells from the cytotoxic effects of bortezomib without compromising its anti-myeloma effects. Schwann cells underwent macroautophagy along with cytoplasmic inclusion body and vacuole formation, and appeared much less susceptible to bortezomib-induced cytotoxicity than did myeloma cells. Vitamin C orN-acetyl-l-cysteine (NAC) achieved near-complete rescue of Schwann cells treated with bortezomib at 30 nM or less, and these agents in combination are able to cooperatively inhibit the morphological changes and the cytotoxicity in Schwann cells with higher doses of bortezomib. The delayed addition of vitamin C and/or NAC after the exposure to bortezomib alleviated the cytotoxicity in Schwann cells but not myeloma cells. These results suggest that delayed treatment with these agents may be instrumental in prophylaxis of BIPN.