丁硫氨酸亚砜胺消耗谷胱甘肽会通过凋亡对人神经母细胞瘤细胞系产生细胞毒性。

Depletion of glutathione by buthionine sulfoxine is cytotoxic for human neuroblastoma cell lines via apoptosis.

作者信息

Anderson C P, Tsai J M, Meek W E, Liu R M, Tang Y, Forman H J, Reynolds C P

机构信息

Division of Hematology-Oncology, Childrens Hospital Los Angeles, 4650 Sunset Boulevard, Los Angeles, California, 90027, USA.

出版信息

Exp Cell Res. 1999 Jan 10;246(1):183-92. doi: 10.1006/excr.1998.4303.

DOI:10.1006/excr.1998.4303

PMID:9882527

Abstract

Buthionine sulfoximine (BSO) selectively inhibits glutathione (GSH) synthesis and has been used to sensitize tumor cells to alkylating agents, but has minimal single-agent cytotoxicity for most cell types. We determined the cytotoxicity of BSO for 18 (12 MYCN amplified; 6 MYCN nonamplified) human neuroblastoma cell lines using DIMSCAN, a digital image microscopy cytotoxicity assay. D-L(R:S) BSO was highly cytotoxic (>3 logs of cell kill) for most neuroblastoma cell lines, with 17/18 cell lines having IC90 values (range 2. 1->1000 microM) below equivalent steady state plasma levels of L(R:S) BSO reported in adult human trials. Cell lines with genomic amplification of MYCN were more sensitive to BSO than MYCN nonamplified cell lines (P = 0.04). D-L(R:S) BSO (500 microM for 72 h) induced apoptosis as detected by DNA laddering, nuclear morphology, and TUNEL staining of DNA fragments using flow cytometry. Maximal cell killing occurred within 48 h and was antagonized byic value in neuroblastoma.

摘要

丁硫氨酸亚砜亚胺（BSO）可选择性抑制谷胱甘肽（GSH）的合成，并已被用于使肿瘤细胞对烷化剂敏感，但对大多数细胞类型的单药细胞毒性极小。我们使用数字图像显微镜细胞毒性测定法DIMSCAN，测定了BSO对18种（12种MYCN扩增；6种MYCN未扩增）人神经母细胞瘤细胞系的细胞毒性。D-L（R:S）BSO对大多数神经母细胞瘤细胞系具有高度细胞毒性（细胞杀伤>3个对数），18种细胞系中有17种的IC90值（范围为2.1->1000微摩尔）低于成人人体试验中报道的L（R:S）BSO的等效稳态血浆水平。MYCN基因扩增的细胞系比MYCN未扩增的细胞系对BSO更敏感（P = 0.04）。D-L（R:S）BSO（500微摩尔，作用72小时）通过DNA梯状条带、核形态学以及使用流式细胞术对DNA片段进行TUNEL染色检测，诱导了细胞凋亡。最大细胞杀伤在48小时内发生，并被神经母细胞瘤中的ic值所拮抗。