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首页> 外文期刊>Cellular Signalling >The combi-targeting concept: Mechanism of action of the pleiotropic combi-molecule RB24 and discovery of a novel cell signaling-based combination principle
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The combi-targeting concept: Mechanism of action of the pleiotropic combi-molecule RB24 and discovery of a novel cell signaling-based combination principle

机译：组合靶向概念：多效性组合分子RB24的作用机理和基于细胞信号的新型组合原理的发现

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RB24 (NSC 741279), a 3-methyltriazene termed "combi-molecule" designed to possess mixed epidermal growth factor receptor (EGFR) targeting and DNA methylating properties showed over a 100-fold greater antiproliferative activity than Temodal? (TEM), a 4-fold greater potency than gefitinib and a 5-fold stronger activity than an equi-effective combination of gefitinib+TEM against the O6-alkylguanine transferase (AGT)-proficient DU145 cell line that co-expresses EGFR. Investigation of the mechanisms underlying the unique potency of RB24 revealed that cell exposure to TEM was accompanied by activation of p38MAPK and concomitant elevation of the levels of X-ray repair cross-complementing group 1 (XRCC1) protein. Levels of phospho-p38MAPK and XRCC1 were increased by 2-fold in EGF-stimulated cells. In contrast, EGF-stimulation did not alter the status of these proteins in RB24-treated cells and this translated into a 2-fold lower level of XRCC1 when compared with those exposed to TEM+EGF. These effects correlated with significantly delayed DNA repair activity in combi-molecule-treated cells when compared with TEM-exposed ones. Further analysis demonstrated that in contrast to TEM, RB24 could block Bad phosphorylation at serine 136 in a dose-dependent manner and induced significantly higher levels of apoptosis than the former molecule. Tandem depletion of XRCC1 and Bad activation through alternative pathways using the MEK1 inhibitor, PD98059, led to substantial levels of apoptosis in RB24-treated cells. The results in toto indicate that the superior activity of the combi-molecule may be attributed to its ability to down-regulate DNA repair proteins such as XRCC1 and to alleviate anti-apoptotic signaling through blockade of EGFR-mediated signaling while inflicting high levels of DNA lesions to the cells.
机译：RB24（NSC 741279）是一种设计为具有混合表皮生长因子受体（EGFR）靶向和DNA甲基化特性的3-甲基三氮烯，称为“复合分子”，其抗增殖活性比Temodal高100倍以上。 （TEM），其功效比吉非替尼高4倍，活性比吉非替尼+ TEM抗O6-烷基鸟嘌呤转移酶（AGT）的共表达EGFR的DU145细胞系有效等效。对RB24独特效能的潜在机制的研究表明，细胞暴露于TEM伴随着p38MAPK的激活和X射线修复交叉互补组1（XRCC1）蛋白水平的升高。在EGF刺激的细胞中，磷酸化p38MAPK和XRCC1的水平增加了2倍。相反，EGF刺激不会改变RB24处理细胞中这些蛋白质的状态，与暴露于TEM + EGF的细胞相比，转化为XRCC1的水平要低2倍。与暴露于TEM的细胞相比，这些效应与经复合分子处理的细胞的DNA修复活性明显延迟有关。进一步的分析表明，与TEM相反，RB24可以剂量依赖性的方式阻断丝氨酸136的Bad磷酸化，并且诱导的凋亡水平明显高于前者。 XRCC1的串联耗尽和使用MEK1抑制剂PD98059通过替代途径的Bad激活导致RB24处理的细胞中大量凋亡。结果表明，该组合分子的优异活性可能归因于其下调DNA修复蛋白（如XRCC1）并通过阻断EGFR介导的信号传导同时破坏高水平DNA减轻抗凋亡信号传导的能力。细胞损伤。

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