Gao Jing-Yan, Chang Chih-Shiang, Lien Jin-Cherng, Chen Ting-Wei, Hu Jing-Lan, Weng Jing-Ru
School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
Drug Development Center, China Medical University, Taichung 40402, Taiwan.
Biomedicines. 2021 Oct 24;9(11):1527. doi: 10.3390/biomedicines9111527.
Trytanthrin, found in Ban-Lan-Gen, is a natural product containing an indoloquinazoline moiety and has been shown to possess anti-inflammatory and anti-viral activities. Chronic inflammation and hepatitis B are known to be associated with the progression of hepatocellular carcinoma (HCC). In this study, a series of tryptanthrin derivatives were synthesized to generate potent anti-tumor agents against HCC. This effort yielded two compounds, A1 and A6, that exhibited multi-fold higher cytotoxicity in HCC cells than the parent compound. Flow cytometric analysis demonstrated that A1 and A6 caused S-phase arrest and downregulated the expression of cyclin A1, B1, CDK2, and p-CDC2. In addition to inducing caspase-dependent apoptosis, A1 and A6 exhibited similar regulation of the phosphorylation or expression of multiple signaling targets, including Akt, NF-κB, and mitogen-activated protein kinases. The anti-tumor activities of A1 and A6 were also attributable to the generation of reactive oxygen species, accompanied by an increase in p-p53 levels. Therefore, A1 and A6 have potential clinical applications since they target diverse aspects of cancer cell growth in HCC.
靛玉红存在于板蓝根中，是一种含有吲哚喹唑啉部分的天然产物，已被证明具有抗炎和抗病毒活性。已知慢性炎症和乙型肝炎与肝细胞癌（HCC）的进展有关。在本研究中，合成了一系列靛玉红衍生物以产生针对HCC的强效抗肿瘤药物。这项工作产生了两种化合物A1和A6，它们在HCC细胞中的细胞毒性比母体化合物高几倍。流式细胞术分析表明，A1和A6导致S期停滞，并下调细胞周期蛋白A1、B1、CDK2和p-CDC2的表达。除了诱导半胱天冬酶依赖性凋亡外，A1和A6对包括Akt、NF-κB和丝裂原活化蛋白激酶在内的多个信号靶点的磷酸化或表达表现出类似的调节作用。A1和A6的抗肿瘤活性还归因于活性氧的产生，同时伴随着p-p53水平的增加。因此，A1和A6具有潜在的临床应用价值，因为它们针对HCC中癌细胞生长的多个方面。
