College of Korean Medicine, Daegu Haany University, Gyeongsan 38610, Korea.
Korean Medicine-Application Center, Korea Institute of Oriental Medicine, Daegu 41062, Korea.
Int J Mol Sci. 2021 Apr 29;22(9):4743. doi: 10.3390/ijms22094743.
(Bunge) Bunge is a biennial medicinal plant possessing beneficial effects including anti-inflammation, and hemistepsin A (HsA) isolated from has been known as a hepatoprotective sesquiterpene lactone. In this report, we explored the cytotoxic effects of on hepatocellular carcinoma (HCC) cells and investigated the associated bioactive compounds and their relevant mechanisms. From the viability results of HCC cells treated with various extracts, HsA was identified as the major compound contributing to the -mediated cytotoxicity. HsA increased expression of cleaved PARP and cells with Sub-G1 phase, Annexin V binding, and TUNEL staining, which imply HsA induces apoptosis. In addition, HsA provoked oxidative stress by decreasing the reduced glutathione/oxidized glutathione ratio and accumulating reactive oxygen species and glutathione-protein adducts. Moreover, HsA inhibited the transactivation of signal transducer and activator of transcription 3 (STAT3) by its dephosphorylation at Y705 and glutathione conjugation. Stable expression of a constitutive active mutant of STAT3 prevented the reduction of cell viability by HsA. Finally, HsA enhanced the sensitivity of sorafenib-mediated cytotoxicity by exaggerating oxidative stress and Y705 dephosphorylation of STAT3. Therefore, HsA will be a promising candidate to induce apoptosis of HCC cells via downregulating STAT3 and sensitizing conventional chemotherapeutic agents.
（ Bunge ） Bunge 是一种两年生药用植物，具有抗炎等有益作用，从其中分离得到的倍半萜内酯化合物 hemistepsin A（HsA）已被证实具有保肝作用。在本报告中，我们探讨了 HsA 对肝癌（HCC）细胞的细胞毒性作用，并研究了相关的生物活性化合物及其相关机制。从用各种 Bunge 提取物处理的 HCC 细胞的活力结果中，鉴定出 HsA 是介导细胞毒性的主要化合物。HsA 增加了裂解 PARP 和具有 Sub-G1 期、Annexin V 结合和 TUNEL 染色的细胞的表达，这意味着 HsA 诱导细胞凋亡。此外，HsA 通过降低还原型谷胱甘肽/氧化型谷胱甘肽比值、积累活性氧和谷胱甘肽-蛋白质加合物来引发氧化应激。此外，HsA 通过其 Y705 去磷酸化和谷胱甘肽结合来抑制信号转导和转录激活因子 3（STAT3）的转录激活。STAT3 的组成性激活突变的稳定表达可防止 HsA 降低细胞活力。最后，HsA 通过夸大氧化应激和 STAT3 的 Y705 去磷酸化来增强索拉非尼介导的细胞毒性的敏感性。因此，HsA 有望通过下调 STAT3 并敏化常规化疗药物来诱导 HCC 细胞凋亡。
