Novel thalidomide analogs: Anti-angiogenic and apoptotic effects on Hep-G2 and MCF-7 cancer cell lines

Roba Talaat , Waheba El-Sayed , Hussein Agwa , Amira Gamal-Eldeen , Shaden Moawia , Magdy Zahran
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引用次数: 15

Abstract

Thalidomide is one of the anti-angiogenic drugs, which have been investigated as a possible treatment for various cancers and diseases. This work aimed to study novel thalidomide analogs for their anti-cytotoxicity, anti-angiogenic, treratogenic gene (FGF-2) expression as well as changes in histone deacetylase (HDAC) activity and nuclear factor kappa-B (NF-κB) level using two different cancer cell lines (Hep-G2 and MCF-7 cells). MTT assay was used to assess the cytotoxic effect of thalidomide analogs against Hep-G2 and MCF-7 cells. HDAC activity was estimated by colorimetric assay. NFκB- P65, pro-angiogenesis and anti-angiogenesis markers were determined by Enzyme-linked immunosorbent assay (ELISA). FGF-2 expression was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Thalidomide dithiocarbamate analogs 1, 5 and thalidomide dithioate analog 3 showed elevation in their cytotoxic activity better than thalidomide. Thalidomide dithioate analog 2 and thalidomide dithiocarbamate analog 4 showed reduction in pro-angiogenic and elevation of anti-angiogenic factors in both cell lines; furthermore, analog 1 is the most potent analog in MCF-7 cells as an anti-angiogenic agent. In Hep-G2 cells, analogs 1, 2, 4 showed a significant increase while analogs 3 and 5 induced a significant decrease in NF-κB level in relation to thalidomide. A drastic decline in HDAC activity was demonstrated in the following order 2 > thalidomide > 1 > 3 > 5 > 4 of the control activity. In conclusion, this study showed that thalidomide analogs are more potent anti-tumor agents with more pronounced effect by working selectively on specific types of tumors than thalidomide.

新型沙利度胺类似物:对Hep-G2和MCF-7癌细胞系的抗血管生成和凋亡作用
沙利度胺是一种抗血管生成药物,已被研究作为多种癌症和疾病的可能治疗方法。本研究旨在利用两种不同的癌细胞系(Hep-G2和MCF-7细胞)研究新型沙利度胺类似物的抗细胞毒性、抗血管生成、致癌性基因(FGF-2)表达以及组蛋白去乙酰化酶(HDAC)活性和核因子κ b (NF-κB)水平的变化。MTT法评估沙利度胺类似物对Hep-G2和MCF-7细胞的细胞毒性作用。用比色法测定HDAC活性。采用酶联免疫吸附法(ELISA)检测促血管生成和抗血管生成标志物NFκB- P65。通过逆转录聚合酶链反应(RT-PCR)证实FGF-2的表达。二硫代氨基甲酸沙利度胺类似物1、5和二硫代沙利度胺类似物3的细胞毒活性比沙利度胺提高得更好。二硫代沙利度胺类似物2和二硫代氨基甲酸沙利度胺类似物4在两种细胞系中均显示促血管生成因子降低和抗血管生成因子升高;此外,类似物1是MCF-7细胞中作为抗血管生成剂最有效的类似物。在Hep-G2细胞中,与沙利度胺相比,类似物1、2、4显著升高,类似物3、5显著降低NF-κB水平。HDAC活性急剧下降的顺序如下2 >萨力多胺比;1比;3比;5比;4 .控制活动。总之,本研究表明,与沙利度胺相比,沙利度胺类似物是一种更有效的抗肿瘤药物,对特定类型的肿瘤具有更明显的选择性作用。
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