Document Type : Research articles


1 PhD, Department of Medical Nursing, College of Nursing, Hebei University of Chinese Medicine, Xingyuan Road, Shijiazhuang, Hebei 050200, P.R. China

2 PhD, Department of Biochemistry and Molecular Biology, College of Basic Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei 050200, China

3 PhD, Department of Oncology, Hebei General Hospital, Shijiazhuang, Hebei 050055, People's Republic of China

4 MD, Ultrasound Department, the Fourth Hospital of Hebei Medical University , NO. 12 Jiankang Road, Shijiazhuang, Hebei 050011, P.R. China

5 PhD, Department of Nephrology, Shijiazhuang Hospital of Traditional Chinese Medicine. Hebei 050051, People's Republic of China


Background: The antitumor mechanism of Rhein has attracted much attention in the current study, and it was found that Rhein could inhibit the growth of the human hepatoma cell line (HepG2).
Objectives: This study aimed to investigate the effect of rhein on the proliferation, invasion, and migration of the HepG2 cells through the extracellular signal-regulated kinase (ERK) signaling pathway.
Methods: HepG2 was treated with different concentrations of rhein (Rhein treatment group) and cultured in a culture medium alone (control group). The proliferation activity of the cells was determined by methyl Thiazolyl Tetrazolium colorimetry. Transwell assay detected the invasion and migration of the cells in each group. Cell scratch test was used to detect the migration ability of cells in each group. Excella-phospho ERK (p-ERK) activity was determined by ELISA after treatment with 50? mol/L rhein at different times. Western blot was employed to detect the ERK protein expression in the HepG2 cells treated with 50 ?mol/L of rhein.
Results: The proliferation activity, invasion, and migration ability of the HepG2 cells in the rhein-treatment group were all decreased, compared to the control group (P<0.05), and the p-ERK relative activity of the HepG2 cells treated with rhein was decreased (P<0.05).
Conclusion: Rhein inhibits the invasion and migration of the hepatocellular carcinoma cells possibly by inhibiting the ERK pathway.


  1. Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A, et al. Global cancer statistics, 2012. CA Cancer J Clin. 2015;65(2):87-108. doi: 10.3322/caac.21262. PMID: 25651787.
  2. Chen W,  Zheng RS,  Baade PD,  Zhang SW, Zeng HM,  Bray F. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115-32. doi: 10.3322/caac.21338. PMID: 26808342
  3. Shen J, He LY, Li C, Wen TF, Chen WX, Lu CL, et al. Nomograms to predict the individual survival of patients with solitary hepatocellularcarcinoma after hepatectomy. Gut Liver. 2017;11(5):684-92. doi: 10.5009/gnl16465. PMID: 28651303.
  4. Lee J, Lee JH, Yoon HB, Lee HJ, Jeon H, Nam J. Extraordinary radiation super sensitivity accompanying with sorafenib combination therapy: what lies beneath?. Radiat Oncol J. 2017;35(2):185-8. doi: 10.3857/roj.2017.00262. PMID: 28712281.
  5. Hsiao JH, Tsai CC, Liang TJ, Chiang CL, Liang HL, Chen IS, et al. Adjuvant hepatic arterial infusion chemotherapy is beneficial for selective patients with hepatocellular carcinoma undergoing surgical treatment. Int J Surg. 2017;(45):35-41. doi: 10.1016/j.ijsu.2017.07.071.
  6. Hao Sun, Luo GW, Chen DH, Xiang Z. Acomprehensive and system review for the pharmacological mechanism of action of rhein, an active anthraquinone ingredient. Front Pharmacol. 2016;17(7): 247.  doi: 10.3389/fphar.2016.00247.PMID: 27582705.
  7. Bi FF, Chen F, Li YN, Wei A, Cao WS. Klotho preservation by Rhein promotes toll-like receptor 4 proteolysis and attenuates lipopolysaccharide induced acute kidney injury. J Mol Med. (Berl.) 2018; 96(9):915-927. doi: 10.1007/s00109-018-1644-7. PMID: 29730698.
  8. Lee S, Han S, Park JS, Jeong AL, YangY. Herb mixture C5E aggravates doxorubicin-induced apoptosis of human breast Cancer cell lines. J Kor Soc Appl Biol Chem. 2013;56(5): 567-573. doi:10.1007/s13765-013-3195-5.
  9. Cho YR, Kim JK, Kim JH, Oh JS, Seo DW. Ligularia fischeri regulates lung cancer cell proliferation and migration through down-regulation of epidermal growth factor receptor and integrinbeta1expression. GenesGenomics. 2013;35(6):741-746. doi:10.1007/s13258-013-0124-2.
  10. Entidhar Al Sawah, Marchion DC, Xiong Y, Ramirez IJ, Abbasi F, Boac BM, et al.The Chinese herb polyphyllin D sensitizes ovarian cancer cells to cisplatin-induced growth arrest. J Cancer Res Clin Oncol. 2015;141(2):237-42. doi: 10.1007/s00432-014-1797-x.
  11. ChangSJ, Huang SH, Lin YJ, Tsou YY, Lin CW. Antiviralactivity of Rheum palmatum methanol extract and chrysophanol againstJapanese encephalitis virus. Arch. Pharm. Res. 2014;37:1117–1123. doi: 10.1007/s12272-013-0325-x.
  12. ZhouYX, Xia W, Yue W, Peng C, Rahman K, Zhang H, et al. Rhein:a review of pharmacological activities. Evid Based Complement Alternat Med. 2015;578107. doi: 10.1155/2015/578107.
  13. Tamura T, Yokoyama T, Ohmori K. Effects of diacerein on indomethacin-induced gastric ulceration. Pharmacology. 2001;63:228. doi: 10.1159/000056138. PMID: 11729361.
  14. Li XH, Li M, Tao YR. Development of pharmacological effects of rhein and its derivatives. Modern medicine and clinic. 2010;25:417. doi:10.7501/j.issn.1674-5515.
  15. Li Y, Xu Y, Lei B, Wang W, Ge X, Li J, et al. Rhein induces apoptosis of human gastric cancer SGC-7901 cells via an intrinsic mitochondrial pathway. Braz J Med Biol Res.        2012;45(11):1052-9.  doi: 10.1590/s0100-879x2012007500125.
  16. Blacher E, Ben Baruch B, Levy A, Geva N, Green KD, Garneau-Tsodikova S, Fridman M, Stein R, et al. Inhibition of glioma progression by a newly discovered CD38 inhibitor. Int J Cancer. 2015;136(6):1422-33. doi: 10.1002/ijc.29095. PMID: 25053177.
  17. Huang HJ, Lin CC, Chou HC, Chen YW, Lin ST, Lin YC, Lin DY, Lyu KW, Chan HL, et al. Proteomic analysis of rhein-induced cyt: ER stress mediates cell death in breast cancer cells. Mol Biosyst. 2014;10(12):3086-100. doi: 10.1039/c4mb00451e.
  18. Chen YY, Chiang SY, Lin JG, Ma YS, Liao CL, Weng SW, Lai TY, Chung JG, et al. Emodin, aloe-emodin and rhein inhibit migration and invasion in human tongue cancer SCC-4 cells through the inhibition of gene expression of matrix metalloproteinase-9. Int J Oncol. 2010;36(5):1113-20. doi: 10.3892/ijo_00000593.
  19. Ip SW, Weng YS, Lin SY, Mei-Dueyang, Tang NY, Su CC, Chung JG, et al. The role of Ca+2 on rhein-induced apoptosis in human cervical cancer Ca Ski cells. Anticancer Res. 2007;27(1A):379-89. PMID: 17352257. PMID: 17352257.
  20. Shi P, Huang Z, Chen G. Rhein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma BEL-7402 cells. Am J Chin Med. 2008;36(4):805-13. doi: 10.1142/S0192415X08006259. PMID: 18711776.