Bulbul Muhammet Volkan, Mermer Arif, Kolbasi Bircan, Kocabas Fatih, Kalender Semiha Mervenur, Kirectepe Aydin Kiymet Asli, Demircan Turan, Keskin İlknur
Department of Histology and Embryology, School of Medicine, Agri Ibrahim Cecen University, Agri 04000, Turkey.
Department of Histology and Embryology, School of Medicine, Istanbul Medipol University, Istanbul 34810, Turkey.
Pharmaceuticals (Basel). 2024 Nov 21;17(12):1562. doi: 10.3390/ph17121562.
Endometrial cancer remains a significant health concern, with type 1 endometrial cancer characterized by aberrant expression of estrogen-dependent and mTOR pathway proteins. In this study, we evaluated the effects of two novel hydrazone derivatives against the Ishikawa cell line, a model for endometrial cancer.
Two novel hydrazone derivatives, MVB1 and MVB2, were synthesized and characterized. The anticancer activity of the compounds in both two- and three-dimensional cultured Ishikawa cells was evaluated by MTT assay. The interaction of the compounds with proteins in the PI3K/AKT/mTOR pathway was evaluated by molecular docking studies and in vitro western blot analyses were performed. Additionally, ADME/T calculations were performed to evaluate the drug-like properties of the compounds.
MVB1 and MVB2 showed promising anticancer activity with IC values of 8.3 ± 0.5 µM and 9.0 ± 1.2 µM in 2D cultures, respectively, and 49.9 ± 2 µM and 20.6 ± 1.9 µM in 3D cultures, respectively. Molecular docking studies revealed significant interactions between these compounds and key proteins in the PI3K/AKT/mTOR pathway, with MVB1 exhibiting the highest mean binding score (-10.5 kcal/mol) among PI3K, AKT1, and mTOR proteins. In vitro studies confirmed that MVB1 effectively suppressed PI3K protein expression in both 2D and 3D cultures ( ≤ 0.0001).
The findings suggest that MVB1 and MVB2, especially MVB1, are promising candidates for further development as potential therapeutics for endometrial cancer by targeting the PI3K/AKT/mTOR pathway.
子宫内膜癌仍然是一个重大的健康问题，1型子宫内膜癌的特征是雌激素依赖性和mTOR通路蛋白的异常表达。在本研究中，我们评估了两种新型腙衍生物对子宫内膜癌模型 Ishikawa 细胞系的影响。
合成并表征了两种新型腙衍生物 MVB1 和 MVB2。通过MTT 法评估化合物在二维和三维培养的 Ishikawa 细胞中的抗癌活性。通过分子对接研究评估化合物与PI3K/AKT/mTOR通路中蛋白质的相互作用，并进行体外蛋白质印迹分析。此外，进行了ADME/T计算以评估化合物的类药性质。
MVB1 和 MVB2 显示出有前景的抗癌活性，在二维培养中IC值分别为8.3±0.5μM和9.0±1.2μM，在三维培养中分别为49.9±2μM和20.6±1.9μM。分子对接研究揭示了这些化合物与PI3K/AKT/mTOR通路中的关键蛋白之间的显著相互作用，MVB1在PI3K、AKT1和mTOR蛋白中表现出最高的平均结合分数（-10.5 kcal/mol）。体外研究证实，MVB1在二维和三维培养中均有效抑制PI3K蛋白表达（≤0.0001）。
研究结果表明，MVB1和MVB2，尤其是MVB1，有望通过靶向PI3K/AKT/mTOR通路进一步开发成为子宫内膜癌的潜在治疗药物。
