Kuete Victor, Sandjo Louis P, Ouete Judith L Nantchouang, Fouotsa Hugues, Wiench Benjamin, 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, Cameroon.
Department of Biochemistry, Faculty of Science, University of Yaoundé I, Cameroon.
Phytomedicine. 2014 Feb 15;21(3):315-22. doi: 10.1016/j.phymed.2013.08.018. Epub 2013 Sep 24.
Resistance of cancer to chemotherapy remains a challenging issue for scientists as well as physicians. Naturally occurring xanthones possess a variety of biological activities such as anti-inflammatory, anti-bacterial, and anti-cancer effects. The present study was aimed at investigating the cytotoxicity and the modes of action of three naturally occurring xanthones namely, morusignin I (1), 8-hydroxycudraxanthone G (2) and cudraxanthone I (3) against a panel of nine cancer cell lines, including various sensitive and drug-resistant phenotypes.
The cytotoxicity of the compounds was determined using a resazurin reduction assay, whereas the caspase-Glo assay was used to detect the activation of caspases 3/7, caspase 8 and caspase 9 in cells treated with compounds 3. Flow cytometry was used for cell cycle analysis and detection of apoptotic cells, analysis of mitochondrial membrane potential (MMP) as well as measurement of reactive oxygen species (ROS).
Compounds 1 and 3 inhibited the proliferation of all tested cancer cell lines including sensitive and drug-resistant phenotypes. Compound 2 was active on 8/9 cell lines with the IC50 values ranging from 16.65 μM (against leukemia CCRF-CEM cells) to 70.38 μM (against hepatocarcinoma HepG2 cells). The IC50 value ranged from 7.15 μM (against CCRF-CEM cells) to 53.85 μM [against human glioblastoma U87MG.ΔEGFR cells] for compound 1, and from 2.78 μM (against breast cancer MDA-MB231 BCRP cells) to 22.49 μM (against U87MG cells) for compound 3. P-glycoprotein expressing CEM/ADR5000 cells were cross-resistant to compounds 1 and 2 (4.21- to 610-fold) while no cross-resistance or even collateral cross-sensitivity were observed in other drug-resistant cell lines to the three compounds. Normal AML12 liver cells were more resistant to the three compounds than HepG2 liver cancer cells. Compounds 3 arrested the cell cycle between G0/G1 and S phases, strongly induced apoptosis via caspases 3/7, caspase 8, caspase 9 activation and disrupted the MMP in CCRF-CEM cells.
The cytotoxicity of the studied xanthones and especially compound 3 deserve more detailed exploration in the future to develop novel anticancer drugs against sensitive and otherwise drug-resistant phenotypes.
癌症对化疗的耐药性仍然是科学家和医生面临的一个具有挑战性的问题。天然存在的呫吨酮具有多种生物活性，如抗炎、抗菌和抗癌作用。本研究旨在研究三种天然存在的呫吨酮，即桑辛素I（1）、8-羟基库拉索酮G（2）和库拉索酮I（3）对一组9种癌细胞系的细胞毒性及其作用方式，这些癌细胞系包括各种敏感和耐药表型。
使用刃天青还原试验测定化合物的细胞毒性，而使用caspase-Glo试验检测用化合物3处理的细胞中caspase 3/7、caspase 8和caspase 9的激活情况。流式细胞术用于细胞周期分析和凋亡细胞检测、线粒体膜电位（MMP）分析以及活性氧（ROS）测量。
化合物1和3抑制了所有测试癌细胞系的增殖，包括敏感和耐药表型。化合物2对8/9种细胞系有活性，IC50值范围为16.65μM（对白血病CCRF-CEM细胞）至70.38μM（对肝癌HepG2细胞）。化合物1的IC50值范围为7.15μM（对CCRF-CEM细胞）至53.85μM[对人胶质母细胞瘤U87MG.ΔEGFR细胞]，化合物3的IC50值范围为2.78μM（对乳腺癌MDA-MB231 BCRP细胞）至22.49μM（对U87MG细胞）。表达P-糖蛋白的CEM/ADR5000细胞对化合物1和2具有交叉耐药性（4.21至610倍），而在其他耐药细胞系中未观察到对这三种化合物的交叉耐药性或甚至协同交叉敏感性。正常AML12肝细胞对这三种化合物的耐药性比HepG2肝癌细胞更强。化合物3使细胞周期停滞在G0/G1和S期之间，通过激活caspase 3/7、caspase 8、caspase 9强烈诱导凋亡，并破坏CCRF-CEM细胞中的MMP。
所研究的呫吨酮尤其是化合物3的细胞毒性在未来值得更详细的探索，以开发针对敏感和其他耐药表型的新型抗癌药物。
