白头翁酸 B 通过抑制多种致癌信号通路对人肝癌细胞表现出抗癌活性。

Pseudolaric acid B exhibits anti-cancer activity on human hepatocellular carcinoma through inhibition of multiple carcinogenic signaling pathways.

机构信息

State Key Laboratory Breeding Base of Systematic Research Development and Utilization of Chinese Medicine Resources, Sichuan Province and Ministry of Science and Technology, Chengdu University of Traditional Chinese Medicine, China.

School of Pharmacy, Southwest Minzu University, Chengdu, China.

出版信息

Phytomedicine. 2019 Jun;59:152759. doi: 10.1016/j.phymed.2018.11.019. Epub 2018 Nov 19.

DOI:10.1016/j.phymed.2018.11.019

PMID:31004883

Abstract

BACKGROUND

Pseudolaric acid B (PAB), a diterpene acid isolated from the root bark of Pseudolarix kaempferi, exhibits a potent anti-cancer activity in a variety of tumor cells.

PURPOSE

The present study was designed to evaluate the anti-cancer effects of PAB on hepatocellular carcinoma (HCC) cell lines in vitro, and to explore the underlying mechanism.

METHODS

The anti-proliferative activity of PAB on HCC cells were assessed via sulforhodamine B staining, colony formation, cell cycle analysis, respectively. Apoptosis was detected using Annexin V/propidium iodide double staining and diamidino-phenyl-indole staining, respectively. Protein expression regulated by PAB treatment was tested by western blotting.

RESULTS

The present results showed that PAB significantly inhibited the proliferation of HepG2, SK-Hep-1, and Huh-7 HCC cell lines in vitro with IC values of 1.58, 1.90, and 2.06 μM, respectively. Furthermore, PAB treatment repressed the colony formation in HepG2, SK-Hep-1, and Huh-7 HCC cell lines. Flow cytometry analysis revealed that PAB caused an obvious cell cycle arrest in G2/M phase and induced apoptosis with the induction of p21, Bax, cleaved-caspase-3, and cleaved-PARP in human HepG2 and SK-Hep-1 cells. Mechanistically, PAB treatment down-regulated the phosphorylation of STAT3, ERK1/2, and Akt. Moreover, abnormal GSK-3β/β-catenin signaling in HepG2 cells was remarkably suppressed by PAB treatment. Finally, proliferation markers including cyclin D1 and c-Myc, and anti-apoptosis proteins such as Bcl-2 and survivin were also down-regulated by PAB treatment in HepG2 cells.

CONCLUSION

Taken together, our results suggest that PAB exerts anti-cancer activity in HCC cells through inhibition of STAT3, ERK1/2, Akt, and GSK-3β/β-catenin carcinogenic signaling pathways, and may be used as a phytomedicine in the treatment of HCC.

摘要

背景

从中国马尾树的根皮中分离得到的土槿皮乙酸（PAB）在多种肿瘤细胞中表现出很强的抗癌活性。

目的

本研究旨在评估 PAB 对体外肝癌（HCC）细胞系的抗癌作用，并探讨其潜在机制。

方法

通过磺酰罗丹明 B 染色、集落形成、细胞周期分析分别评估 PAB 对 HCC 细胞的增殖抑制活性。通过 Annexin V/碘化丙啶双染色和二脒基苯基吲哚染色分别检测细胞凋亡。通过 Western blot 检测 PAB 处理后蛋白表达的变化。

结果

本研究结果表明，PAB 显著抑制 HepG2、SK-Hep-1 和 Huh-7 HCC 细胞系的体外增殖，IC 值分别为 1.58、1.90 和 2.06 μM。此外，PAB 处理抑制了 HepG2、SK-Hep-1 和 Huh-7 HCC 细胞系的集落形成。流式细胞术分析显示，PAB 导致细胞周期明显停滞在 G2/M 期，并诱导人 HepG2 和 SK-Hep-1 细胞中 p21、Bax、cleaved-caspase-3 和 cleaved-PARP 的凋亡。机制上，PAB 处理下调 STAT3、ERK1/2 和 Akt 的磷酸化。此外，PAB 处理显著抑制 HepG2 细胞中异常的 GSK-3β/β-catenin 信号通路。最后，PAB 处理还下调了 HepG2 细胞中的增殖标志物 cyclin D1 和 c-Myc 以及抗凋亡蛋白 Bcl-2 和 survivin。