Kuete Victor, Nkuete Antoine H L, Mbaveng Armelle T, Wiench Benjamin, Wabo Hippolyte K, Tane Pierre, Efferth Thomas
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.
Phytomedicine. 2014 Oct 15;21(12):1651-7. doi: 10.1016/j.phymed.2014.08.001. Epub 2014 Sep 15.
Resistance of cancer to chemotherapy is a main cause in treatment failure. Naturally occurring chalcones possess a wide range of biological activities including anti-cancer effects. In this work, we evaluated the antiproliferative activity of three chalcones [4'-hydroxy-2',6'-dimethoxychalcone (1), cardamomin (2), 2',4'-dihydroxy-3',6'-dimethoxychalcone (3)], and four flavanones [(S)-(-)-pinostrobin (4), (S)-(-)-onysilin (5) and alpinetin (6)] toward nine cancer cell lines amongst which were multidrug resistant (MDR) types.
The resazurin reduction assay was used to detect the antiproliferative activity of the studied samples whilst flow cytometry for the mechanistic studies of the most active molecule (1).
IC50 values in a range of 2.54 μM against CEM/ADR5000 leukemia cells to 58.63 μM toward hepatocarcinoma HepG2 cells were obtained with 1. The lowest IC50 values of 8.59 μM for 2 and 10.67 μM for 3 were found against CCRF-CEM cells leukemia cells, whilst the corresponding values were above 80 μM for 4 and 6. P-glycoprotein-expressing and multidrug-resistant CEM/ADR5000 cells were much more sensitive toward compound 1 than toward doxorubicin and low cross-resistance or even collateral sensitivity was observed in other drug-resistent cell lines to this compound. Normal liver AML12 cells were more resistant to the studied compounds than HepG2 liver cancer cells, indicating tumor specificity at least to some extent. Compound 1 arrested the cell cycle between Go/G1 phase, strongly induced apoptosis via disrupted mitochondrial membrane potential (MMP) and increased production of reactive oxygen species (ROS) in the studied leukemia cell line.
Chalcone 1 was the best tested cytotoxic molecule and further studies will be performed in order to envisage its possible use in the fight against multifactorial resistant cancer cells.
癌症对化疗的耐药性是治疗失败的主要原因。天然存在的查耳酮具有广泛的生物活性，包括抗癌作用。在本研究中，我们评估了三种查耳酮[4'-羟基-2',6'-二甲氧基查耳酮(1)、小豆蔻明(2)、2',4'-二羟基-3',6'-二甲氧基查耳酮(3)]和四种黄烷酮[(S)-(-)-松属素(4)、(S)-(-)-奥尼西林(5)和山姜素(6)]对九种癌细胞系的抗增殖活性，其中包括多药耐药(MDR)类型。
采用刃天青还原法检测所研究样品的抗增殖活性，同时采用流式细胞术对活性最强的分子(1)进行机制研究。
化合物1对CEM/ADR5000白血病细胞的IC50值在2.54 μM范围内，对肝癌HepG2细胞的IC50值为58.63 μM。化合物2对CCRF-CEM白血病细胞的最低IC50值为8.59 μM，化合物3为10.67 μM，而化合物4和6的相应值高于80 μM。表达P-糖蛋白的多药耐药CEM/ADR5000细胞对化合物1的敏感性远高于对阿霉素的敏感性，并且在其他耐药细胞系中观察到对该化合物的低交叉耐药甚至协同敏感性。正常肝脏AML12细胞比肝癌HepG2细胞对所研究的化合物更具耐药性，这表明至少在一定程度上具有肿瘤特异性。化合物1使细胞周期停滞在G0/G1期之间，通过破坏线粒体膜电位(MMP)强烈诱导凋亡，并增加所研究白血病细胞系中活性氧(ROS)的产生。
查耳酮1是测试效果最佳的细胞毒性分子，将进一步开展研究以设想其在对抗多因素耐药癌细胞方面的潜在用途。
