噻吩并[3,2-b]噻吩衍生物诱导小鼠白血病模型细胞凋亡及抑制 Akt 通路。
Bithiophene derivative induced apoptosis and suppression of Akt pathway in mouse leukemic model.
机构信息
Department of Biochemistry, Faculty of Science, Ain Shams University, Cairo, Egypt.
Department of Chemistry, Faculty of Science, Mansoura University, Mansoura, Egypt.
出版信息
Tumour Biol. 2022;44(1):53-67. doi: 10.3233/TUB-211538.
BACKGROUND
Bithiophene derivatives show a promising anti-cancer potential. We previously showed that Bithienyl Fluorobenzamidine (BFB) has an anti-proliferative effect against several leukemia cell lines. Acute myeloid leukemia (AML) accounts for 18% of the total leukemia cases worldwide with heavier burden during the past 30 years. Therefore, the main aim remains the discovery of safe and effective medications.
OBJECTIVE
The current research aims to investigate the anti-cancer efficacy of BFB and its effect on the apoptosis in the 7,12-Dimethylbenz[a]anthracene (DMBA) induced AML in mice.
METHODS
AML was induced in mice by DMBA and then treated by 2 different doses of BFB. After BFB treatment, the hematological and histological pattern changes was examined. Furthermore, the molecular effect of BFB on apoptosis, cell cycle markers and Protein kinase B (Akt) pathway was examined using qPCR, Western blotting and ELISA.
RESULTS
BFB treatment ameliorates leukemia histological and hematological markers significantly, despite non-significant changes in normal mice. This improvement exhibits cell cycle arrest and apoptosis induction, represented by elevation of tp53/p53, p21/p21, Caspase3 and downregulation of ckk1/Cdk1 in the bone marrow, as well as Akt pathway suppression.
CONCLUSIONS
Our results establishes BFB as a promising therapeutic candidate against AML through cell cycle arrest, apoptosis induction and Akt pathway modulation.
背景
噻吩并噻吩衍生物具有很有前途的抗癌潜力。我们之前已经表明，双噻吩氟苯甲脒（BFB）对几种白血病细胞系具有抗增殖作用。急性髓细胞白血病（AML）占全球总白血病病例的 18%，在过去 30 年中负担更重。因此，主要目标仍然是发现安全有效的药物。
目的
本研究旨在研究 BFB 的抗癌功效及其对 7,12-二甲基苯并[a]蒽（DMBA）诱导的 AML 小鼠中细胞凋亡的影响。
方法
用 DMBA 诱导 AML 小鼠，然后用 2 种不同剂量的 BFB 治疗。BFB 治疗后，检查血液学和组织学模式变化。此外，使用 qPCR、Western blot 和 ELISA 检查 BFB 对凋亡、细胞周期标志物和蛋白激酶 B（Akt）通路的分子作用。
结果
BFB 治疗可显著改善白血病的组织学和血液学标志物，尽管对正常小鼠没有明显变化。这种改善表现为细胞周期停滞和凋亡诱导，骨髓中 tp53/p53、p21/p21、Caspase3 的升高和 Cdk1/Cdk1 的下调，以及 Akt 通路的抑制。
结论
我们的研究结果表明，BFB 通过细胞周期停滞、诱导细胞凋亡和调节 Akt 通路，成为治疗 AML 的有前途的候选药物。
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