Pharmacokinetic and Pharmacodynamic Factors Contribute to Synergism between Let-7c-5p and 5-Fluorouracil in Inhibiting Hepatocellular Carcinoma Cell Viability.
Pharmacokinetic and Pharmacodynamic Factors Contribute to Synergism between Let-7c-5p and 5-Fluorouracil in Inhibiting Hepatocellular Carcinoma Cell Viability.
复制标题
DOI：
10.1124/dmd.120.000207
复制
发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Yu AM
中科院分区：
文献类型：
--
作者：
Jilek JL;Tu MJ;Zhang C;Yu AM
肝细胞癌（HCC）的药物干预受到复杂因素的阻碍，合理的联合治疗可能会改善治疗结果。最近，我们已经确定了一种生物工程microRNA let-7 c-5 p（或let-7 c）试剂作为体外和体内抗HCC的有效抑制剂。在这项研究中，我们试图确定可能与let-7 c协同作用对抗HCC的小分子药物。有趣的是，我们发现let-7 c与5-FU在抑制肝癌细胞活力方面表现出较强的协同作用，Hep 3B和Huh 7细胞的平均联合指数分别为0.3和0.5。相比之下，let-7 c与多柔比星或索拉非尼的共同施用抑制HCC细胞活力，而令人惊讶的是，没有或只有最小的协同作用。进一步的研究表明，肝癌细胞中的多药耐药相关蛋白（MRP）ATP结合盒亚家族C成员5（MRP 5/ABCC 5），一种5-FU外排转运蛋白，被let-7 c降低了约50%。这导致Huh 7细胞中5-FU以及第二信使环磷酸腺苷（MRP 5的内源性底物）的细胞内蓄积程度更高。由于5-FU是胸苷酸合成酶（TS）的不可逆抑制剂，我们在药效学水平上研究了let-7 c与5-FU的相互作用。有趣的是，我们的数据显示let-7 c显著降低Huh 7细胞中的TS蛋白水平，这与上游转录因子以及其他调控因子的抑制有关。总的来说，这些结果表明，let-7 c与5-FU在药代动力学和药效学水平上相互作用，这些发现将提供深入了解协同药物组合的分子机制。联合治疗是一种常见的策略，通常涉及药效学相互作用。在确定let-7 c-5 p和5-氟尿嘧啶（5-FU）对肝细胞癌细胞活力之间的强协同作用后，我们揭示了药代动力学和药效学机制的参与。特别是，let-7 c增强5-FU暴露（通过抑制ABCC 5/MRP 5表达），并与5-FU共同靶向胸苷酸合成酶（let-7 c降低蛋白质表达，而5-FU不可逆地使酶失活）。这些发现为基于药理学机制开发合理的联合治疗提供了见解。
Pharmacological interventions for hepatocellular carcinoma (HCC) are hindered by complex factors, and rational combination therapy may be developed to improve therapeutic outcomes. Very recently, we have identified a bioengineered microRNA let-7c-5p (or let-7c) agent as an effective inhibitor against HCC in vitro and in vivo. In this study, we sought to identify small-molecule drugs that may synergistically act with let-7c against HCC. Interestingly, we found that let-7c exhibited a strong synergism with 5-fluorouracil (5-FU) in the inhibition of HCC cell viability as manifested by average combination indices of 0.3 and 0.5 in Hep3B and Huh7 cells, respectively. By contrast, coadministration of let-7c with doxorubicin or sorafenib inhibited HCC cell viability with, rather surprisingly, no or minimal synergy. Further studies showed that protein levels of multidrug resistance–associated protein (MRP) ATP-binding cassette subfamily C member 5 (MRP5/ABCC5), a 5-FU efflux transporter, were reduced around 50% by let-7c in HCC cells. This led to a greater degree of intracellular accumulation of 5-FU in Huh7 cells as well as the second messenger cyclic adenosine monophosphate, an endogenous substrate of MRP5. Since 5-FU is an irreversible inhibitor of thymidylate synthetase (TS), we investigated the interactions of let-7c with 5-FU at pharmacodynamic level. Interestingly, our data revealed that let-7c significantly reduced TS protein levels in Huh7 cells, which was associated with the suppression of upstream transcriptional factors as well as other regulatory factors. Collectively, these results indicate that let-7c interacts with 5-FU at both pharmacokinetic and pharmacodynamic levels, and these findings shall offer insight into molecular mechanisms of synergistic drug combinations. Combination therapy is a common strategy that generally involves pharmacodynamic interactions. After identifying a strong synergism between let-7c-5p and 5-fluorouracil (5-FU) against hepatocellular carcinoma cell viability, we reveal the involvement of both pharmacokinetic and pharmacodynamic mechanisms. In particular, let-7c enhances 5-FU exposure (via suppressing ABCC5/MRP5 expression) and cotargets thymidylate synthase with 5-FU (let-7c reduces protein expression, whereas 5-FU irreversibly inactivates enzyme). These findings provide insight into developing rational combination therapies based on pharmacological mechanisms.
登录
查看更多内容
影响因子：
8
作者：
Kerkhoff, E;Houben, R;Rapp, UR
通讯作者：
Rapp, UR
影响因子：
13.5
作者：
Borel, Florie;Han, Ruiqi;Konstantinova, Pavlina
通讯作者：
Konstantinova, Pavlina
影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
158.5
作者：
Finn, Richard S.;Qin, Shukui;Cheng, Ann-Lii
通讯作者：
Cheng, Ann-Lii
影响因子：
168.9
作者：
Bruix, Jordi;Qin, Shukui;Han, Guohong
通讯作者：
Han, Guohong