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Molecular docking, anti-proliferative activity and induction of apoptosis in human liver cancer cells treated with androstane derivatives: Implication of PI3K/AKT/mTOR pathway.
The Journal of Steroid Biochemistry and Molecular Biology ( IF 4.1 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.jsbmb.2020.105604 Shahad W Kattan 1 , Mohamed S Nafie 2 , Gamal A Elmgeed 3 , Walla Alelwani 4 , Muhammad Badar 5 , Mohamed A Tantawy 6
The Journal of Steroid Biochemistry and Molecular Biology ( IF 4.1 ) Pub Date : 2020-01-23 , DOI: 10.1016/j.jsbmb.2020.105604 Shahad W Kattan 1 , Mohamed S Nafie 2 , Gamal A Elmgeed 3 , Walla Alelwani 4 , Muhammad Badar 5 , Mohamed A Tantawy 6
Affiliation
Worldwide, cancer is still an area with high unmet medical need. Lead optimization efforts towards structure-based drug design were employed to discover newly synthesized hetero-steroid derivatives with promising anticancer effects against hepatocellular carcinoma (HCC). The aim of our study is to evaluate the anti-proliferative activity and the mechanism, a dual PI3K/mTOR inhibitor, and mechanism of action of a series of heterocylic androstane derivatives as anti-HCC agent. The cytotoxic effects of different heterocylic androstanes and 5FU as single agents, were assessed against both HepG2 cells and Non-malignant MDCK cell line to assess the toxicity. Then the underlying mechanism of compound 4 as most promising compound was evaluated using molecular docking, MTT assay, cell cycle analysis, DNA fragmentation, and real-time PCR. The results of MTT assay showed potential cytotoxic effect for compound 4 and 5 against liver cancer cell line with IC50 value 39.81 and 57.54 μM, respectively. Inhibition of the PI3K/AKT/mTOR pathway was achieved by compound 4, which was documented by molecular docking and augmented by gene expression analysis. Detailed mechanism revealed that compound 4 induced cell cycle arrest, DNA fragmentation, and induction of apoptosis by inhibition of anti-apoptotic genes, and upregulation of apoptotic genes. Our results shed a light on aminopyrazoloandrostane derivative 4 as an inhibitor of the PI3K/AKT/mTOR pathway, which might be acting as promising anti-liver cancer agent. Our data support further investigation of agents targeting the PI3K/AKT/mTOR.
中文翻译:
雄激素衍生物处理的人肝癌细胞的分子对接,抗增殖活性和凋亡诱导:PI3K / AKT / mTOR途径的意义。
在世界范围内,癌症仍然是医疗需求未得到满足的领域。进行了基于结构药物设计的前导优化工作,以发现新合成的具有对肝细胞癌(HCC)抗癌作用的杂类固醇衍生物。我们的研究目的是评估其抗增殖活性及其机理,PI3K / mTOR双重抑制剂以及一系列杂环雄烷烃衍生物作为抗HCC药物的作用机理。针对HepG2细胞和非恶性MDCK细胞系评估了不同的杂环雄烷和5FU作为单一药物的细胞毒性作用,以评估毒性。然后使用分子对接,MTT分析,细胞周期分析,DNA片段化和实时PCR评估化合物4作为最有希望的化合物的潜在机理。MTT测定的结果显示化合物4和5对肝癌细胞系的潜在细胞毒性作用,IC 50值分别为39.81和57.54μM。化合物4实现了对PI3K / AKT / mTOR途径的抑制,这通过分子对接进行了记录,并通过基因表达分析得到了增强。详细的机制揭示了化合物4通过抑制抗凋亡基因和上调凋亡基因来诱导细胞周期停滞,DNA片段化和诱导凋亡。我们的研究结果揭示了氨基吡唑并雄烷衍生物4作为PI3K / AKT / mTOR途径的抑制剂,可能是有希望的抗肝癌药物。我们的数据支持对针对PI3K / AKT / mTOR的代理商的进一步调查。
更新日期:2020-01-23
中文翻译:
雄激素衍生物处理的人肝癌细胞的分子对接,抗增殖活性和凋亡诱导:PI3K / AKT / mTOR途径的意义。
在世界范围内,癌症仍然是医疗需求未得到满足的领域。进行了基于结构药物设计的前导优化工作,以发现新合成的具有对肝细胞癌(HCC)抗癌作用的杂类固醇衍生物。我们的研究目的是评估其抗增殖活性及其机理,PI3K / mTOR双重抑制剂以及一系列杂环雄烷烃衍生物作为抗HCC药物的作用机理。针对HepG2细胞和非恶性MDCK细胞系评估了不同的杂环雄烷和5FU作为单一药物的细胞毒性作用,以评估毒性。然后使用分子对接,MTT分析,细胞周期分析,DNA片段化和实时PCR评估化合物4作为最有希望的化合物的潜在机理。MTT测定的结果显示化合物4和5对肝癌细胞系的潜在细胞毒性作用,IC 50值分别为39.81和57.54μM。化合物4实现了对PI3K / AKT / mTOR途径的抑制,这通过分子对接进行了记录,并通过基因表达分析得到了增强。详细的机制揭示了化合物4通过抑制抗凋亡基因和上调凋亡基因来诱导细胞周期停滞,DNA片段化和诱导凋亡。我们的研究结果揭示了氨基吡唑并雄烷衍生物4作为PI3K / AKT / mTOR途径的抑制剂,可能是有希望的抗肝癌药物。我们的数据支持对针对PI3K / AKT / mTOR的代理商的进一步调查。