1,3,6-三羟基-4,5,7-三氯氧杂蒽酮与阿霉素联合对B细胞淋巴瘤细胞的协同作用及其通过分子对接的作用机制
Synergistic Effect of 1,3,6-Trihydroxy-4,5,7-Trichloroxanthone in Combination with Doxorubicin on B-Cell Lymphoma Cells and Its Mechanism of Action Through Molecular Docking.
作者信息
Miladiyah Isnatin, Yuanita Emmy, Nuryadi Satyo, Jumina Jumina, Haryana Sofia Mubarika, Mustofa Mustofa
机构信息
Pharmacology Department, Faculty of Medicine, Universitas Islam Indonesia, Yogyakarta, Indonesia.
Chemistry Department, Faculty of Mathematics and Natural Sciences, Mataram University, Mataram, Indonesia.
出版信息
Curr Ther Res Clin Exp. 2020 Jan 30;92:100576. doi: 10.1016/j.curtheres.2020.100576. eCollection 2020.
BACKGROUND
The increasing rate of cancer chemoresistance and adverse side effects of therapy have led to the wide use of various chemotherapeutic combinations in cancer management, including lymphoid malignancy.
OBJECTIVE
We investigated the effects of a combination of 1,3,6-trihydroxy-4,5,7-trichloroxanthone (TTX) and doxorubicin on the Raji lymphoma cell line.
METHODS
Raji cells were treated with different concentrations of TTX, doxorubicin, or combinations thereof. Cancer cell growth inhibition was evaluated using 3-(4,5-dimethyltiazol-2-yl)-2,5- diphenyltetrazolium bromide/MTT assay to determine the half-maximal inhibitory concentration. Combination index values were calculated using CompuSyn (ComboSyn, Inc, Paramus, NJ). Molecular docking was conducted using a Protein-Ligand ANT System.
RESULTS
The mean (SD) half-maximal inhibitory concentration values of TTX and doxorubicin were 15.948 (3.101) µM and 25.432 (1.417) µM, respectively. The combination index values of the different combinations ranged from 0.057 to 0.285, indicating strong to very strong synergistic effects. The docking study results reveal that TTX docks at the active site of Raf-1 and c-Jun N-kinase receptors with predicted free energies of binding of -79.37 and -75.42 kcal/mol, respectively.
CONCLUSIONS
The xanthone-doxorubicin combination showed promising in vitro activity against lymphoma cells. The results also indicate that the TTX and doxorubicin combination's effect was due to the interaction between TTX with Raf-1 and c-Jun N-kinase receptors, 2 determinants of doxorubicin resistance progression.
背景
癌症化疗耐药率的上升以及治疗的不良副作用导致各种化疗联合方案在癌症治疗中广泛应用，包括淋巴系统恶性肿瘤。
目的
我们研究了1,3,6 - 三羟基 - 4,5,7 - 三氯氧杂蒽酮（TTX）与阿霉素联合应用对Raji淋巴瘤细胞系的影响。
方法
用不同浓度的TTX、阿霉素或其组合处理Raji细胞。采用3 -（4,5 - 二甲基噻唑 - 2 - 基）- 2,5 - 二苯基四氮唑溴盐/MTT法评估癌细胞生长抑制情况，以确定半数最大抑制浓度。使用CompuSyn（ComboSyn公司，新泽西州帕拉默斯）计算联合指数值。使用蛋白质 - 配体ANT系统进行分子对接。
结果
TTX和阿霉素的平均（标准差）半数最大抑制浓度值分别为15.948（3.101）μM和25.432（1.417）μM。不同组合的联合指数值在0.057至0.285之间，表明具有强至非常强的协同作用。对接研究结果显示，TTX分别以预测结合自由能 - 79.37和 - 75.42 kcal/mol对接在Raf - 1和c - Jun N - 激酶受体的活性位点。
结论
氧杂蒽酮 - 阿霉素联合方案对淋巴瘤细胞显示出有前景的体外活性。结果还表明，TTX与阿霉素联合的作用是由于TTX与Raf - 1和c - Jun N - 激酶受体之间的相互作用，这两个受体是阿霉素耐药进展的决定因素。
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