DataSheet_1_Novel Butein Derivatives Repress DDX3 Expression by Inhibiting PI3K/AKT Signaling Pathway in MCF-7 and MDA-MB-231 Cell Lines.pdf

BackgroundBreast cancer is one of the major causes of mortalities noticed in women globally. DDX3 has emerged as a potent target for several cancers, including breast cancer to which currently there are no reported or approved drugs.
MethodsTo find effective cancer therapeutics, three compounds were computationally designed tweaking the structure of natural compound butein. These compounds were synthesized and evaluated for their anticancer property in MCF-7 and MDA-MB-231 cell lines targeting DDX3. The in silico molecular docking studies have shown that the compounds have occupied the binding site of the human DDX3 target. Furthermore, to investigate the cell viability effect of 3a, 3b, and 3c on MCF-7 and MDA-MB-231 cell lines, the cell lines were treated with different concentrations of compounds for 24 and 48 h and measured using MTT assay.
ResultsThe cell viability results showed that the have induced dose dependent suppression of DDX3 expression. Additionally, 3b and 3c have reduced the expression of DDX3 in MCF-7 and MDA-MD-231 cell lines. 3b or 3c treated cell lines increased apoptotic protein expression. Both the compounds have induced the apoptotic cell death by elevated levels of cleaved PARP and cleaved caspase 3 and repression of the anti-apoptosis protein BCL-xL. Additionally, they have demonstrated the G2/M phase cell cycle arrest in both the cell lines. Additionally, 3c decreased PI3K and AKT levels.
ConclusionsOur results shed light on the anticancer ability of the designed compounds. These compounds can be employed as chemical spaces to design new prospective drug candidates. Additionally, our computational method can be adapted to design new chemical scaffolds as plausible inhibitors.

### 背景
乳腺癌是全球女性死亡的主要诱因之一。DDX3已被证实是多种癌症的有效治疗靶点，其中包括目前尚无获批上市治疗药物的乳腺癌。

### 方法
为筛选高效癌症治疗药物，本研究以天然化合物毛蕊花黄素（butein）的结构为骨架进行修饰优化，共设计得到3种化合物。随后对这些化合物进行合成，并在靶向DDX3的MCF-7与MDA-MB-231细胞系中评估其抗癌活性。计算机模拟分子对接研究显示，这些化合物可结合人DDX3靶点的结合口袋。此外，为探究3a、3b、3c对MCF-7与MDA-MB-231细胞系的细胞活力影响，我们用不同浓度的化合物分别处理细胞24小时与48小时，并通过MTT实验检测细胞活力。

### 结果
细胞活力实验结果显示，受试化合物可呈剂量依赖性抑制DDX3的表达。此外，3b与3c可在MCF-7及MDA-MB-231细胞系中降低DDX3的表达水平。经3b或3c处理的细胞系中，凋亡相关蛋白的表达水平显著升高。两种化合物均可通过提升剪切型多聚ADP核糖聚合酶（cleaved PARP）与剪切型半胱氨酸天冬氨酸蛋白酶3（cleaved caspase 3）的表达水平，并抑制抗凋亡蛋白BCL-xL的表达，诱导细胞凋亡。此外，两种化合物均可使两种细胞系阻滞于G2/M细胞周期。同时，3c可降低PI3K与AKT的蛋白表达水平。

### 结论
本研究结果证实了所设计化合物的抗癌活性。这些化合物可作为化学骨架用于开发新型潜在抗癌候选药物。此外，本研究采用的计算设计方法可用于构建新型化学骨架，以开发潜在的DDX3抑制剂。