Effect of 6-aminonicotinamide and other protein synthesis inhibitors on formation of platinum-DNA adducts and cisplatin sensitivity
Effect of 6-aminonicotinamide and other protein synthesis inhibitors on formation of platinum-DNA adducts and cisplatin sensitivity
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DOI：
10.1124/mol.57.3.529
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发表时间：
2000-03-01
影响因子：
3.6
通讯作者：
Kaufmann, SH
中科院分区：
文献类型：
--
作者：
Budihardjo, II;Boerner, SA;Kaufmann, SH
本研究进行了检查的机制基础，最近观察到的吡啶核苷酸衍生物6-氨基烟酰胺（6AN，NSC 21206），提高顺铂在各种肿瘤细胞系中的积累和产生的细胞毒性。当用62.5 μ M 6AN处理A549肺癌细胞或K562白血病细胞21小时，然后用[S-35]甲硫氨酸脉冲标记1小时时，观察到五种多肽的标记增加，其中一种对应于类似于78，000葡萄糖调节蛋白（GRP 78）的M-r。然而，随后的两个观察结果表明，这些多肽的上调不太可能解释6AN和顺铂之间的相互作用：1）诱导GRP 78所需的6AN浓度比使细胞对顺铂敏感所需的剂量高4倍;和2）用6AN和放线菌酮同时处理细胞阻止了GRP 78的增加，但不能阻止6AN的致敏作用。相反，治疗与蛋白质合成抑制剂放线菌酮，茴香霉素，或嘌呤霉素，以及长期暴露于RNA合成抑制剂放线菌素D模仿的生物化学调节作用的6AN对顺铂的作用。相反，6AN抑制蛋白质的合成，而18个6AN类似物，未能提高铂-DNA加合物和顺铂的细胞毒性未能抑制蛋白质的合成。这些观察结果与6AN和其他蛋白质合成抑制剂通过增加顺铂积累而作为调节剂的模型一致，从而增强Pt-DNA加合物的形成和随后的顺铂诱导的细胞死亡。
The present study was undertaken to examine the mechanistic basis for the recent observation that the pyridine nucleotide derivative 6-aminonicotinamide (6AN, NSC 21206) enhances the accumulation and resulting cytotoxicity of cisplatin in a variety of tumor cell lines. When A549 lung cancer cells or K562 leukemia cells were treated with 62.5 mu M 6AN for 21 h and then pulse-labeled with [S-35]methionine for 1 h, increased labeling of five polypeptides, one of which corresponded to a M-r similar to 78,000 glucose-regulated protein (GRP78), was observed. Two subsequent observations, however, suggested that up-regulation of these polypeptides was unlikely to explain the interaction between 6AN and cisplatin: 1) the concentration of 6AN required to induce GRP78 was 4-fold higher than the dose required to sensitize cells to cisplatin; and 2) simultaneous treatment of cells with 6AN and cycloheximide prevented the increase in GRP78 but not the sensitizing effect of 6AN. On the contrary, treatment with the protein synthesis inhibitors cycloheximide, anisomycin, or puromycin as well as prolonged exposure to the RNA synthesis inhibitor actinomycin D mimicked the biochemical modulating effects of 6AN on cisplatin action. Conversely, 6AN inhibited protein synthesis, whereas 18 6AN analogs that failed to enhance Pt-DNA adducts and cisplatin cytotoxicity failed to inhibit protein synthesis. These observations are consistent with a model in which 6AN and other inhibitors of protein synthesis act as modulating agents by increasing cisplatin accumulation, thereby enhancing the formation of Pt-DNA adducts and subsequent cisplatin-induced cell death.