Ludwig Boltzmann Cluster of Translational Oncology, A-1090 Vienna, Austria.
Cancers (Basel). 2014 Jul 8;6(3):1487-99. doi: 10.3390/cancers6031487.
In attempts to develop an orally applicable platinum-based drug, platinum(IV) drugs which exhibit higher in vivo stability compared to the platinum(II) drug cisplatin were formulated. The first such chemotherapeutic agent, namely satraplatin, failed to receive approval. In the present work, we checked the initial cellular stress response of the chemosensitive NCI-H526 small cell lung cancer (SCLC) cells by determination of the relative phosphorylation of 46 specific phosphorylation sites of 38 selected proteins in a six hours response to cisplatin (platinum(II)) or oxoplatin (platinum(IV)), respectively. Oxoplatin is considered as prodrug of cisplatin, although several findings point to differences in intracellular effects. Cisplatin induced hyperphosphorylation of p38α MAPK and AMPKα1, whereas oxoplatin treatment resulted in increased phosphorylation of a large number of signaling proteins involved in stress response/drug resistance, including JNK, GSK-3α, AMPKα1, src kinases, STATs, CHK-2 and especially focal adhesion kinase (FAK). Cisplatin exerts markedly higher cytotoxicity upon four hours short-term exposure in comparison to oxoplatin and, correspondingly, the extended initial stress response to the platinum(IV) drug oxoplatin thus is expected to increase clinical drug resistance. Induction of a substantial stress response to any prodrug of a platinum-based compound may likewise limit the effectivity of its active metabolite(s), such contributing to the failure of selected derivatized platinum complexes.
为了开发可口服的含铂药物，人们设计了铂（IV）药物，与顺铂（铂（II）药物）相比，这些药物在体内更稳定。第一个这样的化疗药物，即 satraplatin，未能获得批准。在本工作中，我们通过测定化疗敏感的 NCI-H526 小细胞肺癌 (SCLC) 细胞对顺铂（铂（II））或奥沙利铂（铂（IV））分别在 6 小时的反应中 38 种选定蛋白的 46 个特定磷酸化位点的相对磷酸化程度，检查了铂（IV）药物的初始细胞应激反应。奥沙利铂被认为是顺铂的前体药物，尽管有一些发现表明其细胞内作用存在差异。顺铂诱导 p38α MAPK 和 AMPKα1 的过度磷酸化，而奥沙利铂处理导致参与应激反应/耐药性的大量信号蛋白磷酸化增加，包括 JNK、GSK-3α、AMPKα1、src 激酶、STATs、CHK-2 特别是粘着斑激酶 (FAK)。与奥沙利铂相比，顺铂在四小时短期暴露时表现出明显更高的细胞毒性，因此，对铂（IV）药物奥沙利铂的扩展初始应激反应预计会增加临床耐药性。任何基于铂的化合物的前体药物引起的实质性应激反应也可能限制其活性代谢物的有效性，从而导致选定的衍生铂络合物的失败。
