title: Delayed treatment with vitamin C and N-acetyl-L-cysteine protects Schwann cells without compromising the anti-myeloma activity of bortezomib.
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.
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Nakano
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan. masabe@clin.med.tokushima-u.ac.jp.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Abe
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Asuka
authors.initials: A
authors.lastname: Oda
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Hiroe
authors.initials: H
authors.lastname: Amou
authors.affiliation: Department of Biomaterials and Bioengineering, University of Tokushima Graduate School of Oral Sciences, Tokushima, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiasa
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Shingen
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Miki
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Harada
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Shirou
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kumiko
authors.initials: K
authors.lastname: Kagawa
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Takeuchi
authors.affiliation: Hematology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Division of Transfusion Medicine, Tokushima University Hospital, Tokushima, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Ozaki
authors.affiliation: Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Medicine, 3-18-15 Kuramoto-cho, Tokushima, 770-8503, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Matsumoto
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D001897:Boronic Acids / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000187:drug effects; D016166:Free Radical Scavengers / Q000008:administration & dosage / Q000494:pharmacology; D009101:Multiple Myeloma / Q000150:complications / Q000188:drug therapy*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced / Q000517:prevention & control; D011719:Pyrazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D012583:Schwann Cells / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D000975:Antioxidants; D001897:Boronic Acids; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D011719:Pyrazines; D000069286:Bortezomib; D001205:Ascorbic Acid; D000111:Acetylcysteine