Tumor Biology

, Volume 35, Issue 4, pp 3053–3060 | Cite as

Anti-hepatoma cells function of luteolin through inducing apoptosis and cell cycle arrest

  • Shixiong Ding
  • Airong Hu
  • Yaoren HuEmail author
  • Jianbo Ma
  • Pengjian Weng
  • Jinhua Dai
Research Article


The aim of this study is to explore the apoptotic induction and cell cycle arrest function of luteolin on the liver cancer cells and the related mechanism. The liver cancer cell line SMMC-7721, BEL-7402, and normal liver cells HL-7702 were treated with different concentrations of luteolin. Cell proliferation ability was tested. Morphological changes of the apoptotic cells were observed under inverted fluorescence microscope after Hoechst33342 staining. We investigated the effect of luteolin on cell cycling and apoptosis with flow cytometry. The mitochondrial membrane potential changes were analyzed after JC-1 staining. Caspases-3 and Bcl-2 family proteins expression were analyzed by real-time PCR. Cell proliferation of SMMC-7721 and BEL-7402 were inhibited by luteolin, and the inhibition was dose–time-dependent. Luteolin could arrest the cells at G1/S stage, reduce mitochondrial membrane potential, and induce higher apoptosis rate and the typical apoptotic morphological changes of the liver carcinoma cells. Q-RT-PCR results also showed that luteolin increased Bax and caspase-3 expression significantly and upregulated Bcl-2 expression in a dose-dependent manner in liver carcinoma cells. However, the normal liver cells HL-7702 was almost not affected by luteolin treatment. Luteolin can inhibit SMMC-7721 and BEL-7402 cell proliferation in a time- and dose-dependent manner. And the mechanism maybe through arresting cell cycle at phase G1/S, enhancing Bax level, reducing anti-apoptotic protein Bcl-2 level, resulting in activating caspase-3 enzyme and decrease of mitochondrial membrane potential, and finally leading to cell apoptosis.


Luteolin Liver cancer Cell apoptosis Cell cycle 


Conflicts of interest



  1. 1.
    Khare S, Zhang Q, Ibdah JA. Epigenetics of hepatocellular carcinoma: role of microRNA. World J Gastroenterol. 2013;19(33):5439–45.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Pratheeshkumar P, Son Y-O, Budhraja A, et al. Luteolin inhibits human prostate tumor growth by suppressing vascular endothelial growth factor receptor 2-mediated angiogenesis. PLoS One. 2012;7(12):e52279.PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Fu J, Chen D, Zhao B, et al. Luteolin induces carcinoma cell apoptosis through binding Hsp90 to suppress constitutive activation of STAT3. PLoS One. 2012;7(11):e49194.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Ju W, Wang X, Shi H, et al. A critical role of luteolin-induced reactive oxygen species in blockage of tumor necrosis factor-activated nuclear factor-kappaB pathway and sensitization of apoptosis in lung cancer cells. Mol Pharmacol. 2007;71:1381–8.PubMedCrossRefGoogle Scholar
  5. 5.
    Cai X, Ye T, Liu C, et al. Luteolin-induced G2 phase cell cycle arrest and apoptosis on non-small cell lung cancer cells. Toxicol In Vitro. 2011;25(7):1385–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Salvioli S, Ardizzoni A, Franceschi C, et al. JC-1, but not DiOC6(3) or rhodamine 123, is a reliable fluorescent probe to assess delta psi changes in intact cells/implications for studies on mitochondrial functionality during apoptosis. FEBS Lett. 1997;411(1):77–82.PubMedCrossRefGoogle Scholar
  7. 7.
    Elumalai P, Gunadharini DN, Senthilkumar K, et al. Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway. Toxicol Lett. 2012;215(2):131–42.PubMedCrossRefGoogle Scholar
  8. 8.
    Leibowitz B, Yu J. Mitochondrial signaling in cell death via the Bcl-2 family. Cancer Biol Ther. 2010;9(6):417–22.PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Das S, Das J, Samadder A, et al. Efficacy of PLGA-loaded apigenin nanoparticles in Benzo[a] pyrene and ultraviolet B-induced skin cancer of mice: mitochondria mediated apoptotic signaling cascades. Food Chem Toxicol. 2013;62C:670–80.CrossRefGoogle Scholar
  10. 10.
    Qin R, Shen H, Cao Y, et al. Tetrandrine induces mitochondria-mediated apoptosis in human gastric cancer BGC-823 cells. PLoS One. 2013;8(10):e76486.PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Kim SM, Kim YG, Park JW, et al. The effects of dexamethasone on the apoptosis and osteogenic differentiation of human periodontal ligament cells. J Periodontal Implant Sci. 2013;43(4):168–76.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Wu W, Li D, Zong Y, et al. Luteolin inhibits inflammatory responses via p38/MK2/TTP-mediated mRNA stability. Molecules. 2013;18(7):8083–94.PubMedCrossRefGoogle Scholar
  13. 13.
    Nazari QA, Kume T, Takada-Takatori Y, et al. Protective effect of luteolin on an oxidative-stress model induced by microinjection of sodium nitroprusside in mice. J Pharmacol Sci. 2013;122(2):109–17.PubMedCrossRefGoogle Scholar
  14. 14.
    Cheng WY, Chiao MT, Liang YJ, et al. Luteolin inhibits migration of human glioblastoma U-87 MG and T98G cells through downregulation of Cdc42 expression and PI3K/AKT activity. Mol Biol Rep. 2013;40(9):5315–26.PubMedCentralPubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Shixiong Ding
    • 1
  • Airong Hu
    • 2
    • 3
  • Yaoren Hu
    • 2
    • 3
    Email author
  • Jianbo Ma
    • 1
  • Pengjian Weng
    • 1
  • Jinhua Dai
    • 1
  1. 1.Department of Laboratory Medicine, The Affiliated Ningbo No.2 HospitalCollege of Medicine, Ningbo UniversityNingboChina
  2. 2.The Affiliated Ningbo No.2 HospitalCollege of Medicine, Ningbo UniversityNingboChina
  3. 3.Institute of Liver DiseaseNingboChina

Personalised recommendations