Ursolic acid combined with HDAC2 inhibitor inhibits proliferation of human hepatoma cell line HepG2

Abstract

Abstract: Objective To investigate the effect of ursolic acid (UA) combined with HDAC2 inhibitor (SA) on the growth and proliferation of human hepatocarcinoma cell line HepG2 and its potential mechanism. Methods CCK-8, optical microscopy, cell clone formation and flow cytometry were used to evaluate the inhibitory effects of UA and SA on HepG2 cells after UA and SA monotherapy or combination therapy. Western blot was used to analyze the expression of HDAC2, AC-α-tubulin CDK2, CDK1, Bax, Bcl-2, and cleaved-PARP in the HepG2 cells after the treatment. Results UA had a significant inhibitory effect on the growth of HepG2 with a concentration and time-dependent manner (P＜0.01); UA inhibited HepG2 cell cloning, and the inhibitory effect was more significant when combined with SA (P＜0.01). UA combined with SA blocked HepG2 cell cycle at G₁ phase (P＜0.01); HDAC2 was highly expressed in human hepatoma SMMC-7721, HepG2, and PLC5 cell lines, and UA combined with SA significantly down-regulated HDAC2, Bcl-2, CDK2 and cyclin E1 protein expression, while up-regulated the expression of AC-α-tubulin, Bax and cleaved-PARP. Conclusions The combined application of UA and SA has a synergistic inhibitory effect on the proliferation of HepG2 cells.

Key words: ursolic acid, liver cancer, histone deacetylase 2 (HDAC2), proliferation

CLC Number:

R735.2

TANG Jia-feng, HE Xue-lian, XIA Jing, XIONG Wei, LI Xiao-shan. Ursolic acid combined with HDAC2 inhibitor inhibits proliferation of human hepatoma cell line HepG2[J]. Basic & Clinical Medicine, 2021, 41(8): 1144-1150.

References

[1]Kern MA, Breuhahn K, Schuchmann M, et al. Molecular pathogenesis of hepatocellular carcinoma: new therapeutic approaches and predictive pathology[J]. Pathologe, 2007, 28: 261-268.
[2]Liu AM, Wu QH, Peng DP, et al. A novel strategy for the diagnosis, prognosis, treatment, and chemoresistance of hepatocellular carcinoma: DNA methylation[J]. Med Res Rev, 2020, 40: 1973-2018.
[3]Cabral LKD, Tiribelli C, Sukowati CHC. Sorafenib resistance in hepatocellular carcinoma: the relevance of genetic heterogeneity[J]. Cancers (Basel), 2020,12:1576. doi: 10.3390/cancers12061576.
[4]Zhang C, Jiang WQ, Ding J. New insights on sorafenib resistance in liver cancer with correlation of individualized therapy[J]. Biochim Biophys Acta Rev Cancer, 2020, 1874: 188382. doi: 10.1016/j.bbcan.2020.188382.
[5]Feng XM, Su XL. Anticancer effect of ursolic acid via mitochondria-dependent pathways[J]. Oncol Lett, 2019, 17: 4761-4767.
[6]雷达,李永利,祁军安.熊果酸对HepG2增殖和凋亡的影响及部分机制研究[J].中国现代普通外科进展,2017,20:259-263.
[7]虞燕霞,尚尔宁,陈伯文.熊果酸通过内质网应激通路诱导肝癌SMMC-7721细胞凋亡[J].江苏医药,2016,42:1000-1003.
[8]Ler SY, Leung CW, Khin LW, et al. HDAC1 and HDAC2 independently predict mortality in hepatocellular carcinoma by a competing risk regression model in a Southeast Asian population[J]. Oncol Rep, 2015, 34: 2238-2250.
[9]周力.熊果酸诱导人肝癌细胞株HepG2凋亡的分子机制研究[J].中国现代医学杂志, 2015,25:24-28.
[10]Khan O, La TNB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications[J]. Immunol Cell Biol, 2012, 90: 85-94.
[11]Yang C, Choy E, Hornicek FJ, et al. Histone deacetylase inhibitor (HDACI) PCI-24781 potentiates cytotoxic effects of doxorubicin in bone sarcoma cells[J]. Cancer Chemother Pharmacol, 2011, 67: 439-446.
[12]Asghar U, Witkiewicz AK, Turner NC, et al. The history and future of targeting cyclin-dependent kinases in cancer therapy[J]. Nat Rev Drug Discov, 2015, 14: 130-146.

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