Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib

Ayako Nakano; Masahiro Abe; Asuka Oda; Hiroe Amou; Masahiro Hiasa; Shingen Nakamura; Hirokazu Miki; Takeshi Harada; Shirou Fujii; Kumiko Kagawa; Kyoko Takeuchi; Takashi Watanabe; Shuji Ozaki; Toshio Matsumoto

doi:10.1007/s12185-011-0850-7

Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib

Int J Hematol. 2011 Jun;93(6):727-735. doi: 10.1007/s12185-011-0850-7. Epub 2011 Apr 28.

Authors

Affiliations

¹ Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
² Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. [email protected].
³ Department of Biomaterials and Bioengineering, University of Tokushima Graduate School of Oral Sciences, Tokushima, Japan.
⁴ Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
⁵ Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan.

PMID: 21526377
DOI: 10.1007/s12185-011-0850-7

Abstract

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 or N-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.

MeSH terms

Acetylcysteine* / administration & dosage
Acetylcysteine* / pharmacology
Animals
Antineoplastic Agents / adverse effects
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Antioxidants / administration & dosage
Antioxidants / pharmacology
Ascorbic Acid* / administration & dosage
Ascorbic Acid* / pharmacology
Autophagy / drug effects
Boronic Acids / adverse effects
Boronic Acids / pharmacology*
Boronic Acids / therapeutic use
Bortezomib
Cell Line
Endoplasmic Reticulum / drug effects
Free Radical Scavengers / administration & dosage
Free Radical Scavengers / pharmacology
Multiple Myeloma / complications
Multiple Myeloma / drug therapy*
Neuroprotective Agents / pharmacology
Neuroprotective Agents / therapeutic use
Peripheral Nervous System Diseases / chemically induced
Peripheral Nervous System Diseases / prevention & control
Pyrazines / adverse effects
Pyrazines / pharmacology*
Pyrazines / therapeutic use
Rats
Schwann Cells / drug effects*

Substances

Antineoplastic Agents
Antioxidants
Boronic Acids
Free Radical Scavengers
Neuroprotective Agents
Pyrazines
Bortezomib
Ascorbic Acid
Acetylcysteine