Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine
Effective treatment of advanced solid tumors by the combination of arsenic trioxide and L-buthionine-sulfoximine
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DOI：
10.1038/sj.cdd.4401389
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发表时间：
2004-07-01
影响因子：
12.4
通讯作者：
Kakizuka, A
中科院分区：
文献类型：
--
作者：
Maeda, H;Hori, S;Kakizuka, A
抗癌药物的临床应用常常受到对正常细胞的毒性的阻碍，因此实现其癌症特异性作用仍然是有待解决的主要挑战之一。以前，我们报道了三氧化二砷（As_2O_3）可能是一个有前途的新药物，不仅对白血病，而且对实体瘤。As_2O_3的细胞毒性是通过产生活性氧（ROS）而发生的，因此，只要正常细胞对这种措施相对耐受，抑制自由基清除系统将增强As_2O_3的治疗效果。在这里，我们报告说，联合治疗的As 2 O3与L-丁硫氨酸-亚砜亚胺（BSO），抑制谷胱甘肽合成的一个关键步骤，有效地增强了体外生长抑制作用的As 2 O3对所有11个研究细胞系产生的前列腺癌，乳腺癌，肺癌，结肠癌，宫颈癌，膀胱癌和肾癌，与单独的As 2 O3治疗。此外，这种组合增强了对前列腺癌细胞系的细胞毒性，而对正常前列腺细胞系的毒性较小。使用ROS相关化合物的体外细胞毒性试验表明，过氧化氢（H2 O2）是ROS分子中的主要细胞毒性介质。生化分析表明，联合使用的As 2 O3和BSO阻断H2 O2-清除系统，包括谷胱甘肽，过氧化氢酶，谷胱甘肽过氧化物酶，这种封锁的程度与细胞内的活性氧水平和敏感性，这种治疗。最后，用原位前列腺癌转移模型证明了As 2 O3与BSO联合治疗的有效性。我们建议，联合治疗的As 2 O3与BSO是一种有效的手段封锁H2 O2-清除系统，和ROS生成剂与主要清除系统的抑制剂的组合是有效的，在疗效和选择性。此外，由于这两种化合物的有效剂量在临床可实现的范围内，该报告将为开发新的癌症治疗带来直接益处。
Clinical application of anticancer agents has been often hampered by toxicity against normal cells, so the achievement of their cancer-specific action is still one of the major challenges to be addressed. Previously, we reported that arsenic trioxide (As2O3) could be a promising new drug against not only leukemia but also solid tumors. The cytotoxicity of As2O3 occurred through the generation of reactive oxygen species (ROS), thus inhibiting radical scavenging systems would enhance the therapeutic efficacy of As2O3 provided that normal cells were relatively resistant to such a measure. Here, we report that the combination therapy of As2O3 with L-buthionine-sulfoximine (BSO), which inhibits a critical step in glutathione synthesis, effectively enhanced in vitro growth inhibition effect of As2O3 on all 11 investigated cell lines arising from prostate, breast, lung, colon, cervix, bladder, and kidney cancers, compared with As2O3 treatment alone. Furthermore, this combination enhanced cytotoxicity to cell lines from prostate cancer with less toxicity to those from normal prostate. In vitro cytotoxic assay using ROS-related compounds demonstrated that hydrogen peroxide (H2O2) is a major cytotoxic mediator among ROS molecules. Biochemical analysis showed that combined use of As2O3 and BSO blocked H2O2-scavenging systems including glutathione, catalase, and glutathione peroxidase, and that the degree of this blockade was well correlated with intracellular ROS levels and sensitivity to this treatment. Finally, the effectiveness of the combination therapy of As2O3 with BSO was demonstrated with an orthotopic model of prostate cancer metastasis. We propose that the combination therapy of As2O3 with BSO is a valid means of blockade of H2O2-scavenging system, and that the combination of a ROS-generating agent with an inhibitor of major scavenging systems is effective in terms of both efficacy and selectivity. Furthermore, because the effective doses of both compounds are within clinically achievable range, this report will lead to immediate benefit for the development of a new cancer therapy.