Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells - The involvement of carbonyl reductase 1 inhibition
Synergistic anticancer activity of doxorubicin and piperlongumine on DU-145 prostate cancer cells - The involvement of carbonyl reductase 1 inhibition
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DOI：
10.1016/j.cbi.2019.01.003
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发表时间：
2019-02-25
影响因子：
5.1
通讯作者：
Pekala, Elzbieta
中科院分区：
文献类型：
--
作者：
Piska, Kamil;Koczurkiewicz, Paulina;Pekala, Elzbieta
化疗失败的原因之一是癌细胞的耐药性。就蒽环类药物而言，已经描述了许多耐药机制。其中一个承担了羰基还原酶 1 (CBR1) 的作用，这是一种胞质酶，负责将蒽环类药物生物转化为活性较低的不良代谢物。因此，CBR1抑制剂被考虑用作化疗增敏剂。在本研究中，研究了荜荠碱 (PL)（一种先前被描述为 CBR1 抑制剂的荜荠生物碱）与阿霉素 (DOX) 联合治疗时的化疗增敏特性。使用人细胞质组分和 LC-MS 跟踪 PL 存在下 DOX 的生物转化过程，然后进行分子建模研究以预测 PL 与 CBR1 活性位点的相互作用。使用 DU-145 前列腺癌细胞研究了 DOX 和 PL 之间的生物相互作用。检查了 DOX 和 PL 的细胞毒性和抗增殖特性，并通过组合指数量化了相互作用的类型和效力。通过流式细胞术研究药物诱导细胞死亡的机制，并通过监测单个细胞的运动来确定药物的抗侵袭特性。 PL 对细胞质中 DOX 代谢表现出剂量依赖性抑制，从而导致形成较少的阿霉素 (DOXol) 代谢物。通过分子模型研究，通过预测酶晶体结构模型活性位点中的 PL 结合模式，解释了 CBR1 抑制的可能机制。 DOX 和 PL 对癌细胞具有协同抗增殖和促凋亡作用。 DOX 和 PL 的组合被发现具有显着的抗侵袭特性，但当这些药物单独使用时，它们并没有改变癌细胞的运动性。细胞运动抑制伴随着细胞骨架结构的显着变化。 DOX和PL联合治疗显示出显着的协同抗癌特性。 PL 对 DOX 代谢的抑制被发现是一种可能导致观察到的相互作用的机制。
One of the causes of therapeutic failure of chemotherapy is cancer cell resistance. In the case of anthracyclines, many resistance mechanisms have been described. One of them assumes the role of carbonyl reductase 1 (CBR1), a cytosolic enzyme that is responsible for the biotransformation process of anthracyclines to less active, undesirable metabolites. Therefore, CBR1 inhibitors are considered for use as a chemosensitizing agents. In the present study, piperlongumine (PL), a Piper longum L. alkaloid that has previously been described as a CBR1 inhibitor, was investigated for its chemosensitizing properties in co-treatment with doxorubicin (DOX). The biotransformation process of DOX in the presence of PL was tracked using human cytosol fraction and LC-MS, then a molecular modeling study was conducted to predict the interaction of PL with the active site of the CBR1. The biological interaction between DOX and PL was investigated using DU-145 prostate cancer cells. Cytotoxic and antiproliferative properties of DOX and PL were examined, and the type and potency of interaction was quantified by Combination Index. The mechanism of the cell death induced by the agents was investigated by flow cytometry and the anti-invasive properties of the drugs were determined by monitoring the movement of individual cells. PL showed dose-dependent inhibition of DOX metabolism in cytosol, which resulted in less doxorubicinol (DOXol) metabolite being formed. The possible mechanism of CBR1 inhibition was explained through molecular modeling studies by prediction of PL's binding mode in the active site of the enzyme's crystal structure-based model. DOX and PL showed a synergistic antiproliferative and proapoptotic effect on cancer cells. Significant anti-invasive properties of the combination of DOX and PL were found, but when the drugs were used separately they did not alter the cancer cells' motility. Cell motility inhibition was accompanied by significant changes in cytoskeleton architecture. DOX and PL used in co-treatment showed significant synergistic anticancer properties. Inhibition of DOX metabolism by PL was found to be a mechanism that was likely to be responsible for the observed interaction.