Browse > Article
http://dx.doi.org/10.4014/mbl.1806.06001

Effects of Psidium guajava Leaf Extract on Apoptosis Induction Through Mitochondrial Dysfunction in HepG2 Cells  

Nguyen, Van-Tinh (Department of Biomedical Engineering, and Centre for Marine-Integrated Biomedical Technology (BK21 Plus))
Ko, Seok-Chun (Team of Marine Bio-resources, National Marine Biodiversity Institute of Korea)
Oh, Gun-Woo (Department of Biomedical Engineering, and Centre for Marine-Integrated Biomedical Technology (BK21 Plus))
Heo, Seong-Yeong (Department of Biomedical Engineering, and Centre for Marine-Integrated Biomedical Technology (BK21 Plus))
Jung, Won-Kyo (Department of Biomedical Engineering, and Centre for Marine-Integrated Biomedical Technology (BK21 Plus))
Publication Information
Microbiology and Biotechnology Letters / v.47, no.1, 2019 , pp. 43-53 More about this Journal
Abstract
The anticancer activity of guava (Psidium guajava L.) leaf extract (GLE) occurs via the induction of apoptosis in cancer cells. However, the mechanism behind GLE-induced apoptosis in the human hepatocellular carcinoma cell line HepG2 remains unclear. In the present study, we investigated the apoptotic effects and mechanism of action of GLE in cultured HepG2 cells. The results showed that GLE induced reactive oxygen species (ROS) synthesis and disrupted the mitochondrial membrane potential (${\Delta}{\Psi}m$). Moreover, GLE increased the expression of apoptotic pathway proteins, such as the cleaved forms of caspase-3, -8, and -9; the translocation of Bax and cytochrome c (cyt-c) from the mitochondria to the cytosol; and the downregulation of Bcl-2. In addition, p53 protein expression was increased upon GLE treatment. These observations indicate that the GLE-induced apoptosis in HepG2 cells is mediated by mitochondrial ROS generation, followed by caspase activation and cyt-c release, suggesting that GLE may be a promising candidate for the development of novel drugs for the treatment of liver cancers.
Keywords
Psidium guajava; apoptosis; HepG2 cells; mitochondrial dysfunction; reactive oxygen species;
Citations & Related Records
연도 인용수 순위
  • Reference
1 Kang ZC, Yen MT, Chiu CK, Wu HC, Huang SL, Tai SP, et al. 2013. The inhibitory effects of aqueous extract from guava twigs, Psidium guajava L., on mutation and oxidative damage. J. Chem. 2013: 561905-561912.
2 Soman S, Rajamanickam C, Rauf AA, Indira M. 2013. Beneficial effects of Psidium guajava leaf extract on diabetic myocardium. Exp. Toxicol. Pathol. 65: 91-95.   DOI
3 Uduak EU, Timbuak JA, Musa SA, Ikyembe DT, Abdurrashid S, Hamman WO. 2012. Ulceroprotective effect of methanol extract of Psidium guajava leaves on ethanol induced gastric ulcer in adult wistar rats. Asian J. Med. Sci. 4: 75-78.
4 Barbalho SM, Farinazzi-Machado FMV, Goulart RA, Brunnati ACS, Ottoboni AMMB, Nicolau CCT. 2012. Psidium Guajava (Guava): A plant of multipurpose medicinal applications. Med. Aromat. Plants 1: 104-110.
5 Shen SC, Cheng FC, Wu NJ. 2008. Effect of guava (Psidium guajava Linn.) leaf soluble solids on glucose metabolism in type 2 diabetic rats. Phytother. Res. 22: 1458-1464.   DOI
6 Lim SW, Kim SW, Lee SC, Yuk HG. 2013. Exposure of Salmonella Typhimurium to guava extracts increases their sensitivity to acidic environments. Food Cont. 33: 393-398.   DOI
7 Lee SB, Park HR. 2010. Anticancer activity of guava (Psidium guajava L.) branch extracts against HT-29 human colon cancer cells. J. Med. Plant Res. 4: 891-896.
8 Rosa MPG, Mitchell S, Solis RV. 2008. Psidium guajava: A review of its traditional uses, phytochemistry and pharmacology. J. Ethnopharmacol. 117: 1-27.   DOI
9 Lee SH, Ryu BM, Je JY, Kim SK. 2011. Diethylaminoethyl chitosan induces apoptosis in HeLa cells via activation of caspase-3 and p53 expression. Carbohydr. Polym. 84: 571-578.   DOI
10 Feng XH, Wang ZH, Meng DL, Li X. 2015. Cytotoxic and antioxidant constituents from the leaves of Psidium quajava. Bioorg. Med. Chem. Lett. 25: 2193-2198.   DOI
11 Park KR, Nam D, Yun HM, Lee SG, Jang HJ, Sethi G, et al. 2011. ${\beta}$-Caryophyllene oxide inhibits growth and induces apoptosis through the suppression of PI3K/AKT/mTOR/S6K1 pathways and ROS-mediated MAPKs activation. Cancer Lett. 312: 178-188.   DOI
12 Yu Z, Li W, Liu F. 2001. Inhibition of proliferation and induction of apoptosis by genistein in colon cancer HT-29 cells. Cancer Lett. 215: 159-166.   DOI
13 Nepal S, Kim MJ, Subedi A, Lee ES, Yong CS, Kim JA, et al. 2012. Globular adiponectin inhibits ethanol-induced apoptosis in HepG2 cells through heme oxygenase-1 induction. Biochem. Pharmacol. 84: 974-983.   DOI
14 Zou Y, Niu P, Yang J, Yuan J, Wu TC, Chen X. 2008. The JNK signaling pathway is involved in sodium-selenite-induced apoptosis mediated by reactive oxygen in HepG2 cells. Cancer Biol. Ther. 7: 691-698.
15 Lee J, Lim KT. 2010. Apoptotic activity of ethanol extract from Styrax Japonica Siebold et al. Zuccarini in HepG2 cells. J. Ethnopharmacol. 131: 210-215.   DOI
16 Chen W, Hou J, Yin Y, Jang J, Zheng Z, Fan H, et al. 2010. ${\alpha}$-Bisabolol induces dose-and time-dependent apoptosis in HepG2 cells via a Fas-and mitochondrial-related pathway, involves p53 and NF-${\kappa}B$. Biochem. Pharmacol. 80: 247-254.   DOI
17 Park C, Jin CY, Hwang HJ, Kim GY, Jung JH, Kim WJ, et al. 2012. J7, a methyl jasmonate derivative, enhances TRAIL-mediated apoptosis through up-regulation of reactive oxygen species generation in human hepatoma HepG2 cells. Toxicol. In Vitro 26: 86-93.   DOI
18 Zou J, Chen Q, Jin X, Tang S, Chen K, Zhang T, et al. 2011. Olaquindox induces apoptosis through the mitochondrial pathway in HepG2 cells. Toxicology 285: 104-113.   DOI
19 Tripathi M, Singh BK, Mishra C, Raisuddin S, Kakkar P. 2010. Involvement of mitochondria mediated pathways in hepatoprotection conferred by Fumaria parviflora Lam. extract against nimesulide induced apoptosis in vitro. Toxicol. In Vitro 24: 495-508.   DOI
20 Zhang P, Li H, Chen D, Ni J, Kang Y, Wang S. 2007. Oleanolic acid induces apoptosis in human leukemia cells through caspase activation and poly (ADP-ribose) polymerase cleavage. Acta Biochim. Biophys. Sin. 39: 803-809.   DOI
21 Lisardo B, Hortelano S. 1999. Mechanisms of nitric oxide-dependent apoptosis: Involvement of mitochondrial mediators. Cell. Signal. 11: 239-244.   DOI
22 Chen X, Liu J, Wang T, Shang J. 2012. Colchicine-induced apoptosis in human normal liver L-02 cells by mitochondrial mediated pathways. Toxicol. In Vitro 26: 649-655.   DOI
23 Chang CH, Hsieh CL, Wang HE, Peng CC, Chyau CC, Peng RY. 2013. Unique bioactive polyphenolic profile of guava (Psidium guajava) budding leaf tea is related to plant biochemistry of budding leaves in early dawn. J. Sci. Food Agric. 93: 944-954.   DOI
24 Poornima P, Quency RS, Padma VV. 2013. Neferine induces reactive oxygen species mediated intrinsic pathway of apoptosis in HepG2 cells. Food Chem. 136: 659-667.   DOI
25 Conde GEA, Nascimento VT, Santos SAB. 2003. Inotropic effects of extracts of Psidium guajava L. (guava) leaves on the guinea pig atrium. Brazil J. Med. Biol. Res. 36: 661-668.   DOI
26 Bontempo P, Doto A, Miceli M, Mita L, Benedetti R, Nebbioso A, et al. 2012. Psidium guajava L. anti-neoplastic effects: induction of apoptosis and cell differentiation. Cell Prolif. 4: 22-31.
27 Liu H, Xiao Y, Xiong C, Wei A, Ruan J. 2011. Apoptosis induced by a new flavonoid in human hepatoma HepG2 cells involves reactive oxygen species-mediated mitochondrial dysfunction and MAPK activation. Eur. J. Pharmacol. 654: 209-216.   DOI
28 Moon JY, Mosaddik A, Kim H, Cho M, Choi HK, Kim YS, et al. 2011. The chloroform fraction of guava (Psidium cattleianumsabine) leaf extract inhibits human gastric cancer cell proliferation via induction of apoptosis. Food Chem. 125: 369-375.   DOI
29 Kaneko K, Suzuki K, Iwadate-Iwata E, Kato I, Uchida K, Onoue M. 2013. Evaluation of food-drug interaction of guava leaf tea. Phytother. Res. 27: 299-305.   DOI
30 Chen KC, Hsieh CL, Peng CC, Hsieh-Li HM, Chiang HS, Huang KD, et al. 2007. Brain derived metastatic prostate cancer DU-145 cells are effectively inhibited in vitro by guava (Psidium gujava L.) leaf extracts. Nutr. Cancer 58: 93-106.   DOI
31 Cao MR, Li Q, Liu ZL, Liu HH, Wang W, Liao XL, et al. 2011. Harmine induces apoptosis in HepG2 cells via mitochondrial signaling pathway. Hepatobiliary. Pancreat. Dis Int. 10: 599-604.   DOI
32 Zhao Q, Guo Y, Feng B, Li L, Huang C, Jiao B. 2011. Neriifolin from seeds of Cerbera manghas L. induces cell cycle arrest and apoptosis in human hepatocellular carcinoma HepG2 cells. Fitoterapia 82: 735-741.   DOI
33 Qiao Y, Xiang Q, Yuan I, Xu L, Liu Z, Liu X. 2013. Herbacetin induces apoptosis in HepG2 cells: Involvements of ROS and PI3K/Akt pathway. Food Chem. Toxicol. 51: 426-433.   DOI
34 Ahmad J, Ahamed M, Akhtar MJ, Alrokayan SA, Siddiqui MA, Musarrat J, et al. 2012. Apoptosis induction by silica nanoparticles mediated through reactive oxygen species in human liver cell line HepG2. Toxicol. Appl. Pharmacol. 259: 160-168.   DOI
35 Yoshitomi H, Guo X, Liu T, Gao M. 2012. Guava leaf extracts alleviate fatty liver via expression of adiponectin receptors in SHRSP.ZLeprfa/Izm rats. Nutr. Metab. 9: 1-13.   DOI
36 Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. 2010. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127: 2893-2917.   DOI
37 Gerets HHJ, Tilmant K, Gerin B, Chanteux H, Depelchin BO, Dhalluin S, et al. 2012. Characterization of primary human hepatocytes, HepG2 cells, and HepaRG cells at the mRNA level and CYP activity in response to inducers and their predictivity for the detection of human hepatotoxins. Cell Biol. Toxicol. 28: 69-87.   DOI
38 Rahman MM, Ahmad SH, Lgu KS. 2012. Psidium guajava and Piper betle leaf extracts prolong vase life of cut carnation (Dianthus caryophyllus) flowers. Sci. World J. 2012: 102805-102814.
39 Raja NRL, Sundar K. 2012. Psidium guajava Linn confers gastro protective effects on rats. Eur. Rev. Med. Pharmacol. Sci. 16: 151-156.
40 Giuliano M, Pellerito O, Portanova P, Calvaruso G, Santulli A, Blasio AD, et al. 2009. Apoptosis induced in HepG2 cells by the synthetic cannabinoid WIN: Involvement of the transcription factor $PPAR{\gamma}$. Biochimie. 91: 457-465.   DOI
41 Yuan L, Kaplowitz N. 2009. Glutathione in liver diseases and hepatotoxicity. Mol. Aspects Med. 30: 29-41.   DOI
42 Menezes C, Alverca E, Dias E, Sam-Bento F, Pereira P. 2013. Involvement of endoplasmic reticulum and autophagy in microcystin- LR toxicity in Vero-E6 and HepG2 cell lines. Toxicol. In Vitro 27: 138-148.   DOI
43 Fink SL, Cookson BT. 2005. Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect. Immun. 73: 1907-1916.   DOI
44 Baqheri E, Hajiaghaalipour F, Nyamathulla S, Salehen N. 2018. The apoptotic effects of Brucea javanica fruit extract against HT29 cells associated with p53 upregulation and inhibition of NF-${\kappa}B$ translocation. Drug Des. Devel. Ther. 12: 657-671.   DOI
45 Ryu NH, Park KR, Kim SM, Yun HM, Nam D, Lee SG, et al. 2012. A hexane fraction of guava leaves (Psidium guajava L.) induces anticancer activity by suppressing AKT/Mammalian target of Rapamycin/Ribosomal p70 S6 kinase in human prostate cancer cells. J. Med. Food 15: 231-241.   DOI
46 Abcam. Introduction to apoptosis. Available from https://www.abcam.com/ps/pdf/protocols/apoptosis_introduction.pdf. Accessed Aug. 24, 2018.
47 Chandrasekaran K, Swaminathan K, Kumar SM, Chatterjee S, Clemens DL, Dey A. 2011. Evated glutathione level does not protect against chronic alcohol mediated apoptosis in recombinant human hepatoma cell line VL-17A over-expressing alcohol metabolizing enzymes-alcohol dehydrogenase and cytochrome P450 2E1. Toxicol. In Vitro 25: 969-978.   DOI
48 Birringer M, Lington D, Vertuani S, Manfredini S, Scharlau D, Gleic M, et al. 2010. Proapoptotic effects of long-chain vitamin E metabolites in HepG2 cells are mediated by oxidative stress. Free Radical Bio. Med. 49: 1315-1322.   DOI