Gümüş Mehmet, Koca İrfan, Sert Yusuf, Dişli Ali, Yenilmez Tunoğlu Ezgi Nurdan, Tutar Lütfi, Tutar Yusuf
Akdağmadeni Health College, Yozgat Bozok University, Yozgat, Türkiye.
Department of Chemistry, Faculty of Arts and Science, Yozgat Bozok University, Yozgat, Türkiye.
J Biomol Struct Dyn. 2023;41(23):14382-14397. doi: 10.1080/07391102.2023.2181643. Epub 2023 Feb 24.
Intensive studies on hepatocellular carcinoma (HCC), which is spreading rapidly around the world and has a high mortality rate, is due to the lack of adequate preventive or curative treatment methods. Treating patients with HCC has become very challenging because of the heterogeneity in the patient population lead activation of different signaling pathways, and pathway crosstalk for patients. Therefore, understanding these molecular mechanisms and combining drugs with molecular therapies to overcome these drawbacks has become an area of utmost importance. In this study, the biological activities of the designed and characterized triad Pyrazole-Thiazol-Coumarin (PTC) compounds were determined by performing cell viability, qPCR array, apoptosis and cell cycle assays. One of the compounds () implicitly suppresses multiple pathways (RAS/MAP kinase and PI3K-AKT) simultaneously. This action is provided by (i) arresting cancer cells at G2 phase, (ii) driving cancer cells to apoptosis and (iii) inhibiting HSP network. Remarkably, HSP is an apoptotic factor and help cancer cell to survive. HSP90 also coordinates with Cdk4/Cdc37, therefore inhibiting HSP both drives cells to arrest and apoptosis. ATP hydrolysis and aggregation assay further displayed specific HSP inhibition. Therefore, PTC provides a unique drug template for HCC treatment.
肝细胞癌（HCC）在全球范围内迅速蔓延且死亡率很高，针对其的深入研究是由于缺乏足够的预防或治疗方法。由于患者群体的异质性导致不同信号通路的激活以及患者的通路串扰，治疗HCC患者变得非常具有挑战性。因此，了解这些分子机制并将药物与分子疗法相结合以克服这些缺点已成为极其重要的领域。在本研究中，通过进行细胞活力、qPCR阵列、凋亡和细胞周期测定来确定所设计和表征的三联体吡唑-噻唑-香豆素（PTC）化合物的生物学活性。其中一种化合物能同时隐含地抑制多种途径（RAS/丝裂原活化蛋白激酶和PI3K-AKT）。这种作用是通过以下方式实现的：（i）将癌细胞阻滞在G2期，（ii）促使癌细胞凋亡，以及（iii）抑制热休克蛋白（HSP）网络。值得注意的是，HSP是一种凋亡因子且有助于癌细胞存活。HSP90还与细胞周期蛋白依赖性激酶4/细胞周期蛋白依赖性激酶结合蛋白37协同作用，因此抑制HSP既会促使细胞停滞又会导致细胞凋亡。ATP水解和聚集测定进一步显示了对HSP的特异性抑制。因此，PTC为HCC治疗提供了一种独特的药物模板。
