8,8-双(去氢枞基)-双阿魏酸酯对一系列人源和动物源癌细胞表现出显著的细胞毒性。
8,8-bis-(Dihydroconiferyl)-diferulate displayed impressive cytotoxicity towards a panel of human and animal cancer cells.
机构信息
Department of Pharmaceutical Biology, Institute of Pharmacy and Biochemistry, University of Mainz, Staudinger Weg 5, 55128 Mainz, Germany; Department of Biochemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
Department of Chemistry, Faculty of Science, University of Dschang, P.O. Box 67, Dschang, Cameroon.
出版信息
Phytomedicine. 2020 Apr 15;70:153215. doi: 10.1016/j.phymed.2020.153215. Epub 2020 Apr 20.
BACKGROUND
Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes.
PURPOSE
The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied.
METHODS
The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (HDCFH-DA) were assessed by flow cytometry.
RESULTS
DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC values all below 6.5 µM. The obtained IC values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53 human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production.
CONCLUSION
The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.
背景
耐药性癌症是化疗的主要障碍，促使科学家们加紧寻找新的药物来攻克表达多药耐药（MDR）表型的细胞系。
目的
本研究旨在评估阿魏酸衍生物 8,8-双（二氢肉桂酰基）-二阿魏酸（DHCF2）对包括人源和动物源的各种敏感和耐药表型的 18 种癌细胞系的增殖抑制潜力。还进一步研究了该化合物诱导细胞死亡的模式。
方法
通过 Resazurin 还原测定（RRA）评估增殖抑制活性、自噬、铁死亡和坏死性细胞死亡。CCRF-CEM 白血病细胞用于所有机制研究。应用半胱天冬酶-Glo 测定法评估半胱天冬酶的活性。通过流式细胞术评估细胞周期分析（PI 染色）、凋亡（ Annexin V/PI 染色）、线粒体膜电位（JC-1）和活性氧（ROS）（HDCFH-DA）。
结果
DHCF2 对所测试的 18 种癌细胞系表现出显著的细胞毒性作用，IC 值均低于 6.5 μM。DHCF2 的 IC 值范围为 1.17 μM（针对 CCRF-CEM 白血病细胞）至 6.34 μM（针对耐药性 HCT116 p53 人结肠腺癌细胞），而参考药物阿霉素的 IC 值范围为 0.02 μM（针对 CCRF-CEM 细胞）至 122.96 μM（针对多药耐药性 CEM/ADR5000 白血病细胞）。DHCF2 的 IC 值低于阿霉素，针对 CEM/ADR5000 细胞和一些黑色素瘤细胞系，如 MaMel-80a 细胞、Mel-2a 细胞、MV3 细胞和 SKMel-505 细胞。DHCF2 通过半胱天冬酶的激活、MMP 的改变和 ROS 产生的增加，在 CCRF-CEM 细胞中诱导自噬和凋亡。
结论
研究中的二阿魏酸 DHCF2 是一种有前途的增殖抑制化合物。它值得进一步深入研究，最终目标是开发一种新的药物来对抗癌症耐药性。
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