Purvalanol A, olomoucine II and roscovitine inhibit ABCB1 transporter and synergistically potentiate cytotoxic effects of daunorubicin in vitro.
Purvalanol A, olomoucine II and roscovitine inhibit ABCB1 transporter and synergistically potentiate cytotoxic effects of daunorubicin in vitro.
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DOI：
10.1371/journal.pone.0083467
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Staud F
中科院分区：
文献类型：
--
作者：
Cihalova D;Hofman J;Ceckova M;Staud F
细胞周期蛋白依赖性激酶抑制剂（CDKi）在抗癌治疗中具有很高的潜在适用性，但其药代动力学的各个方面，特别是其与药物外排转运蛋白的相互作用，尚未进行详细评估。因此，我们研究了5个CDKi（purvalanol A，olomoucine II，roscovitine，flavopiridol和SNS-032）与ABCB 1转运蛋白的相互作用。四种化合物抑制流出的两个ABCB 1底物，Hoechst 33342和柔红霉素，在MDCKII-ABCB 1细胞：Olomoucine II最强烈，其次是roscovitine，purvalanol A，flavopiridol。SNS-032抑制ABCB 1介导的Hoechst 33342外排，但不抑制柔红霉素。此外，purvalanol A，SNS-032和flavopiridol降低了ABCB 1膜制备物中的受刺激的ATP酶活性，而olomoucine II和roscovitine不仅抑制受刺激的ATP酶，而且显著激活基础ABCB 1 ATP酶，表明这两种CDKi是ABCB 1底物。我们进一步揭示了最强的ABCB 1抑制剂（purvalanol A，olomoucine II和roscovitine）协同增强柔红霉素（一种常用的抗癌药物和ABCB 1底物）在MDCKII-ABCB 1细胞以及人癌HCT-8和HepG 2细胞中的抗增殖作用。我们认为，这种明显的协同作用至少部分是由（i）CDKi介导的ABCB 1转运蛋白的抑制导致柔红霉素的细胞内滞留增加和（ii）CDKi的天然细胞毒活性引起的。我们的研究结果表明，共同管理的测试CDKi与抗癌药物的ABCB 1底物可能会允许显着减少剂量的治疗ABCB 1表达肿瘤。
Cyclin-dependent kinase inhibitors (CDKi) have high potential applicability in anticancer therapy, but various aspects of their pharmacokinetics, especially their interactions with drug efflux transporters, have not yet been evaluated in detail. Thus, we investigated interactions of five CDKi (purvalanol A, olomoucine II, roscovitine, flavopiridol and SNS-032) with the ABCB1 transporter. Four of the compounds inhibited efflux of two ABCB1 substrates, Hoechst 33342 and daunorubicin, in MDCKII-ABCB1 cells: Olomoucine II most strongly, followed by roscovitine, purvalanol A, and flavopiridol. SNS-032 inhibited ABCB1-mediated efflux of Hoechst 33342 but not daunorubicin. In addition, purvalanol A, SNS-032 and flavopiridol lowered the stimulated ATPase activity in ABCB1 membrane preparations, while olomoucine II and roscovitine not only inhibited the stimulated ATPase but also significantly activated the basal ABCB1 ATPase, suggesting that these two CDKi are ABCB1 substrates. We further revealed that the strongest ABCB1 inhibitors (purvalanol A, olomoucine II and roscovitine) synergistically potentiate the antiproliferative effect of daunorubicin, a commonly used anticancer drug and ABCB1 substrate, in MDCKII-ABCB1 cells as well as in human carcinoma HCT-8 and HepG2 cells. We suggest that this pronounced synergism is at least partly caused by (i) CDKi-mediated inhibition of ABCB1 transporter leading to increased intracellular retention of daunorubicin and (ii) native cytotoxic activity of the CDKi. Our results indicate that co-administration of the tested CDKi with anticancer drugs that are ABCB1 substrates may allow significant dose reduction in the treatment of ABCB1-expressing tumors.
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影响因子：
4
作者：
Dai, Y;Grant, S
通讯作者：
Grant, S
影响因子：
6.4
作者：
Appleyard, Maria Virginia C. L.;O'Neill, Mary A.;Thompson, Alastair M.
通讯作者：
Thompson, Alastair M.
影响因子：
45.3
作者：
Lin, Thomas S.;Ruppert, Amy S.;Byrd, John C.
通讯作者：
Byrd, John C.
影响因子：
--
作者：
Holcakova, Jitka;Tomasec, Peter;Vojtesek, Borivoj
通讯作者：
Vojtesek, Borivoj
DOI：
10.1073/pnas.78.1.363
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
LALANDE, ME;LING, V;MILLER, RG
通讯作者：
MILLER, RG