Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, 06330, Ankara, Turkey.
Present address, Department of Pharmacy, Faculty of Medicine and Health Sciences, An-Najah National University, Nablus, Palestine.
Chem Biodivers. 2021 May;18(5):e2001037. doi: 10.1002/cbdv.202001037. Epub 2021 Apr 14.
Hepatocellular carcinoma (HCC) is the most prevalent primary liver cancer and one of the leading causes of cancer associated death worldwide. This is due to the highly resistant nature of this malignancy and the lack of effective treatment options for advanced stage HCC patients. The hyperactivity of PI3K/Akt and Ras/Raf/MEK/ERK signaling pathways contribute to the cancer progression, survival, motility, and resistance mechanisms, and the interaction of these two pathways are responsible for the regulation of cancer cell growth and development. Therefore, it is vital to design and develop novel therapeutic options for HCC treatment targeting these hyperactive pathways. For this purpose, novel series of trans-indole-3-ylacrylamide derivatives originated from the lead compound, 3-(1H-indole-3-yl)-N-(3,4,5-trimethoxyphenyl)acrylamide, have been synthesized and analyzed for their bioactivity on cancer cells along with the lead compound. Based on the initial screening, the most potent compounds were selected to elucidate their effects on cellular signaling activity of HCC cell lines. Cell cycle analysis, immunofluorescence, and Western blot analysis revealed that lead compound and (E)-N-(4-tert-butylphenyl)-3-(1H-indole-3-yl)acrylamide induced cell cycle arrest at the G2/M phase, enhanced chromatin condensation and PARP-cleavage, addressing induction of apoptotic cell death. Additionally, these compounds decreased the activity of ERK signaling pathway, where phosphorylated ERK1/2 and c-Jun protein levels diminished significantly. Relevant to these findings, the lead compound was able to inhibit tubulin polymerization as well. To conclude, the novel trans-indole-3-ylacrylamide derivatives inhibit one of the critical pathways associated with HCC which results in cell cycle arrest and apoptosis in HCC cell lines.
肝细胞癌（HCC）是最常见的原发性肝癌，也是全球癌症相关死亡的主要原因之一。这是由于这种恶性肿瘤具有高度耐药性，以及晚期 HCC 患者缺乏有效治疗选择。PI3K/Akt 和 Ras/Raf/MEK/ERK 信号通路的过度活跃促进了癌症的进展、存活、迁移和耐药机制，并且这两条通路的相互作用负责调节癌细胞的生长和发育。因此，设计和开发针对这些过度活跃通路的 HCC 治疗新疗法至关重要。为此，已经合成了一系列源自先导化合物 3-(1H-吲哚-3-基)-N-(3,4,5-三甲氧基苯基)丙烯酰胺的新型反式吲哚-3-基丙烯酰胺衍生物，并对其在癌细胞中的活性以及先导化合物进行了分析。基于初步筛选，选择最有效的化合物来阐明它们对 HCC 细胞系细胞信号活性的影响。细胞周期分析、免疫荧光和 Western blot 分析表明，先导化合物和 (E)-N-(4-叔丁基苯基)-3-(1H-吲哚-3-基)丙烯酰胺诱导细胞周期停滞在 G2/M 期，增强染色质凝聚和 PARP 切割，导致诱导细胞凋亡。此外，这些化合物降低了 ERK 信号通路的活性，其中磷酸化 ERK1/2 和 c-Jun 蛋白水平显著降低。与这些发现相关的是，先导化合物还能够抑制微管蛋白聚合。总之，新型反式吲哚-3-基丙烯酰胺衍生物抑制了与 HCC 相关的关键途径之一，导致 HCC 细胞系中的细胞周期停滞和细胞凋亡。
