Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner.
Protein kinase inhibitors emodin and dichloro-ribofuranosylbenzimidazole modulate the cellular accumulation and cytotoxicity of cisplatin in a schedule-dependent manner.
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DOI：
10.1007/s00280-009-1045-2
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发表时间：
2010-02
影响因子：
3
通讯作者：
Siddik, Zahid H.
中科院分区：
文献类型：
--
作者：
Kurokawa, Tetsuji;He, Guangan;Siddik, Zahid H.
蛋白激酶抑制剂（PKI）已成为癌症治疗中的重要药物。然而，靶激酶抑制的特异性可能较差，并且在联合治疗方案中可能出现不必要的效果。例如，PKI大黄素与顺铂联合使用时可以产生混合结果，我们已经寻求了对负细胞毒性作用的生化药理学解释。将人卵巢A2780肿瘤细胞暴露于大黄素或二氯核呋喃基苯并咪唑（DRB）和顺铂，并通过生长抑制实验确定细胞毒性。用无焰原子吸收分光光度法测定细胞内铂含量和DNA加合物。当A2780细胞首先暴露于大黄素或DRB，然后单独暴露于顺铂时，顺铂的细胞毒性作用显著增强，而同时暴露于DRB时，并没有增强细胞毒性，反而抑制细胞毒性。在测序计划中，顺铂活性的增加不是由于细胞内顺铂或DNA加合物水平的增加，而细胞毒性抑制与细胞内铂水平和DNA加合物的显著下降有关，这归因于顺铂摄取的抑制。siRNA敲低hCtr1（人类铜转运蛋白1）可消除这种对顺铂摄取的抑制作用。结果表明，肿瘤细胞与顺铂共同暴露于大黄素或DRB可通过影响hCtr1转运体抑制铂类药物的摄取，从而降低顺铂的细胞毒性。根据我们的研究结果，在临床设计联合方案时，PKI和细胞毒性药物的调度应该是一个主要考虑因素。
Protein kinase inhibitors (PKI) have become prominent agents in cancer therapeutics. However, the specificity for target kinase inhibition can be poor and unwanted effects can emerge in combination regimens. The PKI emodin, for instance, can produce mixed results when combined with cisplatin, and we have sought a biochemical pharmacologic explanation for the negative cytotoxic effects. Human ovraian A2780 tumor cells were exposed to the PKI emodin or dichloro-ribofuranosylbenzimidazole (DRB) with cisplatin using several schedules, and cytotoxicity determined by a growth inhibition assay. Intracellular platinum levels and DNA adducts were estimated by flameless atomic absorption spectrophotomotery. When A2780 cells were exposed first to emodin or DRB and then to cisplatin alone, the cytotoxic effects of cisplatin were significantly enhanced, whereas simultaneous exposure did not enhance the cytotoxicity, but instead inhibited it in the case of DRB. The increase in activity of cisplatin in the sequenced schedule was not due to increases in intracellular levels of cisplatin or DNA adducts, whereas the cytotoxic inhibition was related to a significant fall in both intracellular platinum levels and DNA adducts, which were ascribed to inhibition in cisplatin uptake. Knockdowm of hCtr1 (the human copper transporter 1) by siRNA abrogated this inhibition in cisplatin uptake. The results demonstrate that co-exposure of tumor cells to emodin or DRB with cisplatin inhibits platinum drug uptake by impacting the hCtr1 transporter and, thereby, reduce the cytotoxicity of cisplatin. Based on our findings, scheduling of the PKI and the cytotoxic agent should be a major consideration in the clinical design of combination regimens.
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影响因子：
8.8
作者：
通讯作者：
--
DOI：
10.1111/j.1432-1033.1990.tb15280.x
发表时间：
1990-01-12
期刊：
EUROPEAN JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
MEGGIO, F;SHUGAR, D;PINNA, LA
通讯作者：
PINNA, LA
影响因子：
4.8
作者：
Roosbeek, S;Peelman, F;Rosseneu, M
通讯作者：
Rosseneu, M
影响因子：
3.5
作者：
BOSSEMEYER, D
通讯作者：
BOSSEMEYER, D
影响因子：
11.2
作者：
Leggas, Markos;Panetta, John C.;Stewart, Clinton F.
通讯作者：
Stewart, Clinton F.