Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi
Buthionine sulfoximine increases the toxicity of nifurtimox and benznidazole to Trypanosoma cruzi
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DOI：
10.1128/aac.49.1.126-130.2005
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发表时间：
2005-01-01
影响因子：
4.9
通讯作者：
Maya, JD
中科院分区：
文献类型：
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作者：
Faundez, M;Pino, L;Maya, JD
L-丁硫氨酸(S，右)-亚磺胺(BSO)增加了硝呋莫司和苯硝唑对克氏锥虫上鞭毛体、锥虫体和无鞭毛体的毒性。在寄生体中，500um BSO使抑制寄生虫持续生长所需的硝呋莫司浓度下降了50%，从14.0降至9.0um，苯硝唑浓度从43.6um降至24.1 um。用四甲基偶氮唑蓝[3-(4，5-二甲基噻唑-2-基)-2，5-二苯基四氮唑，溴]还原测定，500 um BSO可显著降低经硝呋莫司或苯硝唑处理的表鞭毛体或类鞭毛体的存活率。在感染无鞭毛体的Vero细胞中，25um BSO能够增强硝呋莫司和苯硝唑的作用，其方法是用感染Vero细胞的百分比乘以细胞内无鞭毛体的平均数量(内吞指数)。在0.5微米的硝呋莫司中，加入25微米的BSO，Vero细胞的感染率从27%下降到20%，吞噬指数从2500下降到980。苯硝唑和BSO-苯硝唑处理的细胞也得到了类似的结果。本研究表明，BSO对硝呋莫司或苯硝唑的强化治疗可减少两种药物的临床剂量，减少副作用或缩短疗程。
L-Buthionine (S,R)-sulfoximine (BSO) increased the toxicity of nifurtimox and benznidazole toward the epimastigote, trypomastigote, and amastigote forms of Trypanosoma cruzi. BSO at 500 muM decreased total glutathione-derived thiols by 70 to 80% in 48 h. In epimastigotes, 500 muM BSO decreased the concentration of nifurtimox needed to inhibit constant growth of the parasites by 50%, from 14.0 to 9.0 muM and decreased that of benznidazole from 43.6 to 24.1 muM. The survival of epimastigotes or trypomastigotes treated with nifurtimox or benznidazole, as measured by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium, bromide) reduction, was significantly decreased by 500 muM BSO. In Vero cells infected with amastigotes, 25 muM BSO was able to potentiate the effect of nifurtimox and benznidazole as measured by the percentage of infected Vero cells multiplied by the average number of intracellular amastigotes (endocytic index). At 0.5 muM nifurtimox, the proportion of Vero cells infected decreased from 27 to 20% and the endocytic index decreased from 2,500 to 980 when 25 muM BSO was added. Similar results were obtained with benznidazole- and BSO-benznidazole-treated cells. This study indicates that potentiation of nifurtimox or benznidazole by BSO could decrease the clinical dose of both drugs and diminish the side effects or the length of therapy.