Chrysin induces cell apoptosis via activation of the p53/Bcl‑2/caspase‑9 pathway in hepatocellular carcinoma cells

Zhang,Qingyu; Ma,Sheng; Liu,Bin; Liu,Jie; Zhu,Runzhi; Li,Mingyi

doi:10.3892/etm.2016.3282

Chrysin induces cell apoptosis via activation of the p53/Bcl‑2/caspase‑9 pathway in hepatocellular carcinoma cells

Authors:
- Qingyu Zhang
- Sheng Ma
- Bin Liu
- Jie Liu
- Runzhi Zhu
- Mingyi Li
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Affiliations: Laboratory of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
Published online on: April 20, 2016 https://doi.org/10.3892/etm.2016.3282
Pages: 469-474

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Abstract

Chrysin is a major active ingredient of flavonoids, known to exhibit protective effects against various types of cancer. However, the anticancer role of chrysin against hepatocellular carcinoma (HCC) and the underlying molecular mechanisms remain unclear. In order to evaluate the effects of chrysin on cell viability and apoptosis in human HCC, HepG2 and QGY7701 cells were used in the present study. Cell viability was monitored using an MTT assay. In addition, an Annexin V‑fluorescein isothiocyanate/propidium iodide kit was used for the labeling of the apoptotic cells, which were then measured using flow cytometry. Western blotting was used to examine the protein expression of p53, B‑cell lymphoma‑2 (Bcl‑2), Bcl‑2‑associated X (Bax), Bcl‑2‑associated death promoter (Bad), Bcl‑2 homologous antagonist/killer (Bak), caspases‑3 and ‑9, and cleaved‑caspases‑3 and ‑9. The results of the present study revealed that chrysin suppressed the cell viability of HepG2 and QGY7701 cells in a concentration‑dependent manner. In addition, chrysin induced significant apoptosis in HepG2 and QGY7701 cells. Furthermore, it was demonstrated that chrysin treatment increased the expression of proapoptotic proteins, including p53, Bax, Bad and Bak, while it decreased the protein level of antiapoptotic protein Bcl‑2. It was also demonstrated that chrysin induced apoptosis in the HCC cells by regulating the p53/Bcl‑2/caspase‑9 signaling pathway. In conclusion, the results of the present study suggested that chrysin may be a potential candidate agent for the induction of cell apoptosis in human HCC.

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1	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Forner A, Llovet JM and Bruix J: Hepatocellular carcinoma. Lancet. 379:1245–1255. 2012. View Article : Google Scholar : PubMed/NCBI
3	Au JS and Frenette CT: Management of hepatocellular carcinoma: Current status and future directions. Gut Liver. 9:437–448. 2015. View Article : Google Scholar : PubMed/NCBI
4	Fitzmorris P, Shoreibah M, Anand BS and Singal AK: Management of hepatocellular carcinoma. J Cancer Res Clin Oncol. 141:861–876. 2015. View Article : Google Scholar : PubMed/NCBI
5	Manfredi JJ and Horwitz SB: Taxol: An antimitotic agent with a new mechanism of action. Pharmacol Ther. 25:83–125. 1984. View Article : Google Scholar : PubMed/NCBI
6	Pichichero E, Cicconi R, Mattei M, Muzi MG and Canini A: Acacia honey and chrysin reduce proliferation of melanoma cells through alterations in cell cycle progression. Int J Oncol. 37:973–981. 2010.PubMed/NCBI
7	Barbarić M, Mišković K, Bojić M, Lončar MB, Smolčić-Bubalo A, Debeljak Z and Medić-Šarić M: Chemical composition of the ethanolic propolis extracts and its effect on HeLa cells. J Ethnopharmacol. 135:772–778. 2011. View Article : Google Scholar : PubMed/NCBI
8	Khan R, Khan AQ, Qamar W, Lateef A, Tahir M, Rehman MU, Ali F and Sultana S: Chrysin protects against cisplatin-induced colon toxicity via amelioration of oxidative stress and apoptosis: Probable role of p38MAPK and p53. Toxicol Appl Pharmacol. 258:315–329. 2012. View Article : Google Scholar : PubMed/NCBI
9	Cherkaoui-Tangi K, Lachkar M, Wibo M, Morel N, Gilani AH and Lyoussi B: Pharmacological studies on hypotensive, diuretic and vasodilator activities of chrysin glucoside from Calycotome villosa in rats. Phytother Res. 22:356–361. 2008. View Article : Google Scholar : PubMed/NCBI
10	Song MY, Jeong GS, Kwon KB, Ka SO, Jang HY, Park JW, Kim YC and Park BH: Sulfuretin protects against cytokine-induced beta-cell damage and prevents streptozotocin-induced diabetes. Exp Mol Med. 42:628–638. 2010. View Article : Google Scholar : PubMed/NCBI
11	Tahir M and Sultana S: Chrysin modulates ethanol metabolism in Wistar rats: A promising role against organ toxicities. Alcohol Alcohol. 46:383–392. 2011. View Article : Google Scholar : PubMed/NCBI
12	Yang F, Jin H, Pi J, Jiang JH, Liu L, Bai HH, Yang PH and Cai JY: Anti-tumor activity evaluation of novel chrysin-organogermanium (IV) complex in MCF-7 cell. Bioorg Med Chem Lett. 23:5544–5551. 2013. View Article : Google Scholar : PubMed/NCBI
13	Wen S, Zhu D and Huang P: Targeting cancer cell mitochondria as a therapeutic approach. Future Med Chem. 5:53–67. 2013. View Article : Google Scholar : PubMed/NCBI
14	Brunelle JK and Letai A: Control of mitochondrial apoptosis by the Bcl-2 family. J Cell Sci. 122:437–441. 2009. View Article : Google Scholar : PubMed/NCBI
15	Mu R, Lu N, Wang J, Yin Y, Ding Y, Zhang X, Gui H, Sun Q, et al: An oxidative analogue of gambogic acid-induced apoptosis of human hepatocellular carcinoma cell line HepG2 is involved in its anticancer activity in vitro. Eur J Cancer Prev. 19:61–67. 2010. View Article : Google Scholar : PubMed/NCBI
16	Alenzi FQ, Alenazi BQ, Al-Anazy FH, Mubaraki AM, Salem ML, Al-Jabri AA, Lotfy M, Bamaga MS, Alrabia MW and Wyse RK: The role of caspase activation and mitochondrial depolarisation in cultured human apoptotic eosinophils. Saudi J Biol Sci. 17:29–36. 2010. View Article : Google Scholar : PubMed/NCBI
17	Wolf BB, Schuler M, Echeverri F and Green DR: Caspase-3 is the primary activator of apoptotic DNA fragmentation via DNA fragmentation factor-45/inhibitor of caspase-activated DNase inactivation. J Biol Chem. 274:30651–30656. 1999. View Article : Google Scholar : PubMed/NCBI
18	Fan TJ, Han LH, Cong RS and Liang J: Caspase family proteases and apoptosis. Acta Biochim Biophys Sin (Shanghai). 37:719–727. 2005. View Article : Google Scholar : PubMed/NCBI
19	Ling Y, Lu N, Gao Y, Chen Y, Wang S, Yang Y and Guo Q: Endostar induces apoptotic effects in HUVECs through activation of caspase-3 and decrease of Bcl-2. Anticancer Res. 29:411–417. 2009.PubMed/NCBI
20	Slee EA, Adrain C and Martin SJ: Executioner caspase-3, −6, and −7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J Biol Chem. 276:7320–7326. 2001. View Article : Google Scholar : PubMed/NCBI
21	Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ: Bcl-2, Bcl-X(L) sequester BH3 domain-only molecules preventing BAX and BAK-mediated mitochondrial apoptosis. Mol Cell. 8:705–711. 2001. View Article : Google Scholar : PubMed/NCBI
22	Degenhardt K, Chen G, Lindsten T and White E: BAX and BAK mediate p53 independent suppression of tumorigenesis. Cancer Cell. 2:193–203. 2002. View Article : Google Scholar : PubMed/NCBI
23	Liu J, Shu Y, Zhang Q, Liu B, Xia J, Qiu M, Miao H, Li M and Zhu R: Dihydromyricetin induces apoptosis and inhibits proliferation in hepatocellular carcinoma cells. Oncol Lett. 8:1645–1651. 2014.PubMed/NCBI
24	Henry H, Thomas A, Shen Y and White E: Regulation of the mitochondrial checkpoint in p53 mediated apoptosis confers resistance to cell death. Oncogene. 21:748–760. 2002. View Article : Google Scholar : PubMed/NCBI