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5‐fluorouracil‐induced oligodendrocyte death and inhibitory effect of cycloheximide, trolox, and Z‐VAD‐FMK in murine cortical culture
Author(s) -
Cho KiHyun,
Choi SungMin,
Kim ByeongChae,
Lee SeungHan,
Park ManSeok,
Kim MyeongKyu,
Kim JongKeun
Publication year - 2004
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.20114
Subject(s) - oligodendrocyte , trolox , nbqx , cycloheximide , astrocyte , programmed cell death , pharmacology , medicine , neuroprotection , glutamate receptor , ampa receptor , biology , microbiology and biotechnology , endocrinology , apoptosis , biochemistry , oxidative stress , receptor , central nervous system , protein biosynthesis , myelin , antioxidant capacity
BACKGROUND 5‐fluorouracil (5‐FU) is a widely used anticancer drug. One of the adverse effects of this drug is selective cerebral white matter injury, but to the authors' knowledge its mechanism has not been well documented. The current study was performed to investigate the mechanism of cerebral white matter injury caused by 5‐FU and to develop the intervention to attenuate its injury in vitro. METHODS Mixed oligodendrocyte/astrocyte cells were dissociated from specimens taken from approximately 2‐day‐old postnatal mouse cortex and cultured for 3–4 weeks. The culture cells were exposed to 5‐FU, cycloheximide, emetine, Z‐VAD‐fmk, 2,3‐dihydroxy‐6‐nitro‐7‐sulfamoyl‐benzo(F)‐quinoxaline (NBQX), Trolox, and epigallocatechin gallate. Oligodendrocyte cell death was assessed by counting the number of viable galactocerebroside‐positive cells per × 100 field. RESULTS Mixed oligodendrocyte/astrocyte culture cells that were exposed to 5‐FU (at doses of 10 μM, 30 μM, and 100 μM) for 24 hours ensued concentration‐dependent oligodendrocyte death. The majority of oligodendrocytes, but few astrocytes, were injured by 100 μM 5‐FU. Trolox, a vitamin E analog antioxidant, as well as cycloheximide (a protein synthesis inhibitor) and Z‐VAD‐fmk (a caspase inhibitor), significantly attenuated the 5‐FU–induced oligodendrocyte death. However, NBQX, an alpha‐amino‐2,3‐dihydro‐5‐methyl‐3‐oxo‐4‐isoxazolepropionic acid (AMPA) receptor antagonist, did not appear to effect the 5‐FU–induced oligodentrocyte death. CONCLUSIONS The findings of the current study suggested that 5‐FU led to oligodendrocyte death rather than astrocyte death by way of the apoptotic process, whereas antioxidants may prevent the 5‐FU–induced oligodendrocyte cell death in vitro. Cancer 2004;100:1484–90. © 2004 American Cancer Society.