Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer
Individual dose and scheduling determine the efficacy of combining cytotoxic anticancer agents with a kinase inhibitor in non-small-cell lung cancer
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DOI：
10.1007/s00432-012-1220-4
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发表时间：
2012-04
影响因子：
3.6
通讯作者：
J. Meiler;M. Guyot;S. Hoffarth;Emmanuelle Wesarg;Y. Höhn;F. Breitenbuecher;M. Schuler
中科院分区：
文献类型：
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作者：
J. Meiler;M. Guyot;S. Hoffarth;Emmanuelle Wesarg;Y. Höhn;F. Breitenbuecher;M. Schuler
PurposeTo探讨联合应用常规细胞毒性抗癌药物和小分子激酶抑制剂在非小细胞肺癌（NSCLC）临床前模型中的作用。方法我们比较了6种不同组织学和遗传背景的NSCLC细胞系中DNA损伤性抗癌药物和蛋白激酶C（PKC）特异性小分子抑制剂PKC 412对细胞凋亡的诱导作用。研究了DNA损伤剂和PKC 412的各种组合和时间表的结果，并计算了等效线图。促凋亡巴克的条件性表达被施加到具体的目标凋亡信号转导与药物therapy.ResultsNSCLC细胞的DNA损伤诱导的凋亡的抗性主要是确定在线粒体步骤的内在途径的caspase激活。PKC 412可有效抑制生长因子信号转导，但不能诱导耐DNA损伤剂的NSCLC细胞凋亡。将常规抗癌药物与PKC 412以不同的剂量和时间表组合导致不可预测的结果，包括协同、相加和拮抗相互作用。相反，巴克的条件性表达可使耐药NSCLC细胞对细胞毒药物或PKC 412诱导的凋亡敏感。结论联合使用DNA损伤性抗癌药物和生长和生存因子信号传导抑制剂治疗NSCLC可能导致不可预测的治疗结果。相反，靶向特定的死亡效应机制，如凋亡信号转导，是一种有前途的策略，使NSCLC细胞毒性药物或激酶抑制剂敏感。
PurposeTo investigate the combination of conventional cytotoxic anticancer agents and a small molecule kinase inhibitor in preclinical models of non-small-cell lung cancer (NSCLC).MethodsWe compared the induction of apoptosis by DNA-damaging anticancer drugs and PKC412, a predominantly protein kinase C (PKC)-specific small molecule inhibitor, in six NSCLC cell lines of different histologic and genetic backgrounds. The outcome of various combinations and schedules of DNA-damaging agents and PKC412 was studied, and isobolograms were calculated. Conditional expression of pro-apoptotic BAK was applied to specifically target apoptotic signal transduction in combination with drug therapy.ResultsResistance of NSCLC cells to DNA damage–induced apoptosis was mainly determined at the mitochondrial step of the intrinsic pathway of caspase activation. PKC412 effectively inhibited the growth factor signal transduction, but failed to induce apoptosis in NSCLC cells resistant to DNA-damaging agents. Combining conventional anticancer drugs with PKC412 at different doses and schedules resulted in unpredictable outcomes, including synergistic, additive, and antagonistic interactions. In contrast, conditional expression of BAK reliably sensitized drug-resistant NSCLC cells to apoptosis induced by cytotoxic agents or PKC412.ConclusionsCombining DNA-damaging anticancer drugs with a pharmacologic inhibitor of growth and survival factor signaling in NSCLC may result in unpredictable treatment outcomes. In contrast, targeting specific death effector mechanisms, such as apoptotic signal transduction, is a promising strategy to sensitize NSCLC to cytotoxic agents or kinase inhibitors.