Potential anti-tumor activity of kefir-induced juglone and resveratrol fractions against Ehrlich ascites carcinoma-bearing BALB/c mice

Document Type : Research article

Authors

1 Department of Internal Medicine, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

2 Department of Anatomy, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

3 Department of Hematology, Faculty of Medicine, Mugla Sitki Kocman University, 48000, Muğla, Turkey.

4 Department of Emergency Medicine, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

5 Department of Medical Biochemistry, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

6 Department of Chemistry, Faculty of Arts and Sciences, Yildiz Technical University, 34220, Istanbul, Turkey.

7 Department of Biology, Faculty of Science, Karamanoglu Mehmetbey University, 70100, Karaman, Turkey.

8 Department of Histology, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

9 Department of Biochemistry, Faculty of Medicine, Karabük University, 78020, Karabük, Turkey.

10 Department of Medical Pharmacology, Faculty of Medicine, Afyonkarahisar Health Sciences University, 03200, Afyonkarahisar, Turkey.

Abstract

We investigated the potential influence of kefir-induced juglone and resveratrol fractions (JRK) against Ehrlich Ascites Carcinoma (EAC) bearing BALB/c male mice. Kefir yeast was grown in the cell culture supplemented with juglone and resveratrol (1:2). After 48 hours incubation, JRK solution was applied (0.1 ml/day i.p.) to the EAC-bearing mice throughout five days. Molecular regulatory mechanisms of apoptotic and anti-apoptotic pathway components were evaluated in the plasma of mice and isolated EAC cells with ELISA, qRT-PCR and immunocytchemical experiments. EAC-induced upregulation in Bcl-2 and downregulation in Caspase-3 were normalized with JRK in the plasma of mice. Additionally, JRK upregulated the expression levels of apoptotic Bax, p53, Caspase-3,8,9, and APAF-1 proteins together with BAX, CASPASE-8, and CASPASE-9 genes in isolated EAC cells. These changes were also associated with decreased expression levels of anti-apoptotic Bcl-2 and Bcl-xl proteins. Immunocytochemical studies also confirmed the activation of apoptotic pathways and repression of anti-apoptotic proteins in EAC cells with JRK treatment. JRK activates apoptotic pathway and inhibits anti-apoptotic genes and proteins in Ehrlich ascites carcinoma- bearing BALB/c mice that could be benefical in cancer treatment.

Graphical Abstract

Potential anti-tumor activity of kefir-induced juglone and resveratrol fractions against Ehrlich ascites carcinoma-bearing BALB/c mice

Keywords


  • Torres G, Zakhary SM and Leheste JR. An evolutionary perspective of neoplastic diseases in the universe. Cureus (2019) 11: e4030.
  • El-Far M, Salah N, Essam A, Abd El-Azim A, Karam M and El-Sherbiny IM. Potential anticancer activity and mechanism of action of nano formulated curcumin in experimental Ehrlich Ascites Carcinoma-bearing animals. Nanomedicine (London) (2019) 14: 553–73.
  • Eisa NH, Said HS, ElSherbiny NM, Eissa LA and El-Shishtawy MM. Phenethylisothiocyanate triggers apoptosis, combats oxidative stress and inhibits growth of Ehrlich Ascites Carcinoma mouse model. J. Pharm. Res. (2018) 17: 1328–38.
  • Verma AS, Singh A, Mallick P and Dwivedi PD. Cysteine supplementation mitigates the toxicity associated with antitumor therapy of Ehrlich's ascites fluid adsorbed over protein containing Staphylococcus aureus Cowan I. Pharm. Bioallied. Sci. (2019) 11: 23–32.
  • Mishra S, Tamta AK, Sarikhani M, Desingu PA, Kizkekra SM, Pandit AS, Kumar S, Khan D, Raghavan SC and Sundaresan NR. Subcutaneous Ehrlich Ascites Carcinoma mice model for studying cancer-induced cardiomyopathy. Rep. (2018) 8: 5599.
  • Gupta M, Mazumder UK, Kumar RS, Sivakumar T and Vamsi ML. Antitumor activity and antioxidant status of Caesalpiniabonducella against Ehrlich Ascites Carcinoma in Swiss albino mice. Pharmacol. Sci. (2004) 94: 177–84.
  • Taneja S and Qazi G. Bioactive molecules in medicinal plants: a perspective in their therapeutic action. In: Drug Discovery and Development. Chorghade MS (Ed.) JohnWiley and Sons, Inc, New Jersey, USA (2007) 1: 1–50.
  • Bortolotti C, Kunit T, Moder A, Hufnagl C, Schmidt S, Hartl A, Langelueddecke C, Fürst J, Geibel JP, Ritter M and Jakab M. The phytostilbene resveratrol induces apoptosis in INS-1E rat insulinoma cells. Physiol. Biochem. (2009) 23: 245–54.
  • Santandreu FM, Valle A, Oliver J and Roca P. Resveratrol potentiates the cytotoxic oxidative stress induced by chemotherapy in human colon cancer cells. Physiol. Biochem. (2011) 28: 219–28.
  • Bayram D, Ozgocmen M, Armagan I, Sevimli M, Türel GY and Şenol N. Investigation of apoptotic effect of juglone on CCL-228-SW 480 colon cancer cell line. Cancer Res. Ther. (2019) 15: 68–74.
  • Fang F, Chen S, Ma J, Cui J, Li Q, Meng G and Wang L. Juglone suppresses epithelial-mesenchymal transition in prostate cancer cells via the protein kinase B/glycogensynthase kinase-3β/Snail signalling pathway. Lett. (2018) 16: 2579–84.
  • Yousef M, Vlachogiannis IA and Tsiani E. Effects of resveratrol against lung cancer: in vitro and in vivo studies. Nutrients (2017) 9: E1231.
  • Rauf A, Imran M, Suleria HAR, Ahmad B, Peters DG and Mubarak MS. A comprehensive review of the health perspectives of resveratrol. Food Funct. (2017) 8: 4284–305.
  • Kumar S, Eroglu E, Stokes JA 3rd, Scissum-Gunn K, Saldanha SN, Singh UP, Manne U, Ponnazhagan S and Mishra MK. Resveratrol induces mitochondria-mediated, caspase-independent apoptosis in murine prostate cancer cells. Oncotarget (2017) 8: 20895–908.
  • Zhao H, Han L, Jian Y, Ma Y, Yan W, Chen X, Xu H and Li L. Resveratrol induces apoptosis in human melanoma cells through negatively regulating Erk/PKM2/Bcl-2 axis. Targets Ther. (2018) 11: 8995–9006.
  • Luo H, Yang A, Schulte BA, Wargovich MJ and Wang GY. Resveratrol induces premature senescence in lung cancer cells via ROS-mediated DNA damage. PLoS One (2013) 8: e60065.
  • Velioğlu-Oğünç A, Sehirli O, Toklu HZ, Ozyurt H, Mayadağli A, Ekşioğlu-Demiralp E, Erzik C, Cetinel S, Yeğen BC and Sener G. Resveratrol protects against irradiation-induced hepatic and ileal damage via its anti-oxidative activity. Free Radic. Res. (2009) 43: 1060–71.
  • Avci E, Arikoglu H and Erkoc-Kaya D. Investigation of juglone effects on metastasis and angiogenesis in pancreatic cancer cells. Gene (2016) 588: 74–8.
  • Hu YG, Shen YF and Li Y. Effect of Pin1 inhibitor juglone on proliferation, migration and angiogenic ability of breast cancer cell line MCF7Adr. Huazhong Univ. Sci. Technolog. Med. Sci. (2015) 35: 531–4.
  • Jha BK, Jung HJ, Seo I, Suh SI, Suh MH and Baek WK. Juglone induces cell death of Acanthamoeba through increased production of reactive oxygen species. Parasitol. (2015) 159: 100–6.
  • Meskelevicius D, Sidlauskas K, Bagdonaviciute R, Liobikas J and Majiene D. Jugloneexerts cytotoxic, anti-proliferative and anti-invasive effects on glioblastoma multiforme in a cell culture model. Anticancer Agents Med. Chem. (2016) 16: 1190–7.
  • Ahmad T and Suzuki YJ. Juglone in oxidative stress and cell signalling. Antioxidants (Basel) (2019) 8: E91.
  • Jordens J, Janssens V, Longin S, Stevens I, Martens E, Bultynck G, Engelborghs Y, Lescrinier E, Waelkens E, Goris J and Van Hoof C. The protein phosphatase 2A phosphatase activator is a novel peptidyl-prolylcis/trans-isomerase. Biol. Chem. (2006) 281: 6349–57.
  • Esnault S, Braun RK, Shen ZJ, Xiang Z, Heninger E, Love RB, Sandor M and Malter JS. Pin1 modulates the type 1 immune response. PLoS One (2007) 2: e226.
  • Esnault S, Rosenthal LA, Shen ZJ, Sedgwick JB, Szakaly RJ, Sorkness RL and Malter JS. A critical role for Pin1 in allergic pulmonary eosinophilia in rats. Allergy Clin. Immunol. (2007) 120: 1082–8.
  • Fan G, Fan Y, Gupta N, Matsuura I, Liu F, Zhou XZ, Lu KP and Gélinas C. Peptidyl-prolylisomerase Pin1 markedly enhances the oncogenic activity of the rel proteins in the nuclear factor-kappa B family. Cancer Res. (2009) 69: 4589–97.
  • Kim G, Khanal P, Kim JY, Yun HJ, Lim SC, Shim JH and Choi HS. COT phosphorylates prolyl-isomerase Pin1 to promote tumorigenesis in breast cancer. Carcinog. (2015) 54: 440–8.
  • Nechama M, Uchida T, MorYosef-Levi I, Silver J and Naveh-Many T. The peptidyl-prolylisomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism. Clin. Invest. (2009) 119: 3102–14.
  • Jeong HG, Pokharel YR, Lim SC, Hwang YP, Han EH, Yoon JH, Ahn SG, Lee KY and Kang KW. Novel role of Pin1 induction in type II collagen-mediated rheumatoid arthritis. Immunol. (2009) 183: 6689–97.
  • Liu X, Liang E, Song X, Du Z, Zhang Y and Zhao Y. Inhibition of Pin1 alleviates myocardial fibrosis and dysfunction in STZ-induced diabetic mice. Biophys Res. Commun. (2016) 479: 109–15.
  • Wu D, Huang D, Li LL, Ni P, Li XX, Wang B, Han YN, Shao XQ, Zhao D, Chu WF and Li BY. TGF-β1-PML SUMOylation-peptidyl-prolylcis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis. Cell. Physiol. (2019) 234: 6263–73.
  • Wu X, Li M, Chen SQ, Li S and Guo F. Pin1 facilitates isoproterenol-induced cardiac fibrosis and collagen deposition by promoting oxidative stress and activating the MEK1/2-ERK1/2 signal transduction pathway in rats. J. Mol. Med. (2018) 41: 1573–83.
  • Xu HL, Yu XF, Qu SC, Zhang R, Qu XR, Chen YP, Ma XY and Sui DY. Anti-proliferative effect of Juglone from Juglansmandshurica Maxim on human leukemia cell HL-60 by inducing apoptosis through the mitochondria-dependent pathway. J. Pharmacol. (2010) 645: 14–22.
  • Ji YB, Xin GS, Qu ZY, Zou X and Yu M. Mechanism of juglone-induced apoptosis of MCF-7 cells by the mitochondrial pathway. Mol. Res. (2016) 15
  • Powis G. Free radical formation by antitumor quinones. Free Radic. Biol. Med. (1989) 6: 63–101.
  • Liu X, Chen Y, Zhang Y, Du J, Lv Y, Mo S, Liu Y, Ding F, Wu J and Li J. Juglone potentiates TRAIL-induced apoptosis in human melanoma cells via activating the ROS/p38/p53 pathway. Med. Rep. (2017) 16: 9645–51.
  • Seminario-Amez M, López-López J, Estrugo-Devesa A, Ayuso-Montero R and Jané-Salas E. Probiotics and oral health: A systematic review. Oral Patol. Oral Cir. Bucal. (2017) 22: e282-88.
  • Dimidi E, Christodoulides S, Scott SM and Whelan K. Mechanisms of action of probiotics and the gastrointestinal microbiota on gut motility and constipation. Nutr. (2017) 8: 484–94.
  • Fiorda FA, de Melo Pereira GV, Thomaz-Soccol V, Rakshit SK, Pagnoncelli MGB, Vandenberghe LPS and Soccol CR. Microbiological, biochemical, and functional aspects of sugary kefir fermentation- A review. Food Microbiol. (2017) 66: 86–95.
  • Daniluk U. Probiotics, the new approach for cancer prevention and/or potentialization of anti-cancer treatment. Clin. Exp. Oncol. (2012) 1: 1000e105.
  • Kumar M, Nagpal R, Verma V, Kumar A, Kaur N, Hemalatha R, Gautam SK and Singh B. Probiotic metabolites as epigenetic targets in the prevention of colon cancer. Rev. (2013) 71: 23–34.
  • Ghoneum M and Gimzewski J. Apoptotic effect of a novel kefir product, PFT, on multidrug-resistant myeloid leukaemia cells via a hole-piercing mechanism. J. Oncol. (2014) 44: 830–37.
  • Pektas MB, Turan Ö, Öztürk G, Şumlu E, Sadi G, Yıldırım OG and Akar F. High-glucose causes vascular dysfunction through Akt/eNOS pathway: Reciprocal modulation by juglone and resveratrol. J. Physiol. Pharmacol. (2018) 96: 757-64.
  • Rakici O, Kiziltepe U, Coskun B, Aslamaci S and Akar F. Effects of resveratrol on vascular tone and endothelial function of human saphenous vein and internal mammary artery. J. Cardiol. (2005) 105: 209-15.
  • Coskun B, Soylemez S, Parlar AI, TulgaUlus A, FehmiKatircioglu S andAkar F. Effect of resveratrol on nitrate tolerance in isolated human internal mammary artery. Cardiovasc. Pharmacol. (2006) 47: 437-45.
  • Chiasson VL, Munshi N, Chatterjee P, Young KJ and Mitchell BM. Pin1 deficiency causes endothelial dysfunction and hypertension. Hypertension (2011) 58: 431-38.
  • Ruan L, Torres CM, Qian J, Chen F, Mintz JD, Stepp DW, Fulton D and Venema RC. Pin1 prolylisomerase regulates endothelial nitric oxide synthase. Thromb. Vasc. Biol. (2011) 31: 392-8.
  • MacLimans WF, Davis EV, Glover FL and Rake GW. The submerged culture of mammalian cells: the spinner culture. Immunol. (1957) 79: 428–33.
  • Pektas MB, Koca HB, Sadi G and Akar F. Dietary fructose activates insulin signaling and inflammation in adipose tissue: Modulatory role of resveratrol. Res. Int. (2016) 2016: 8014252.
  • Pelicano H, Carney D and Huang P. ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat. (2004) 7: 97–110.
  • Gaikwad S, Chakraborty A, Salwe S, Patel V, Kulkarni S and Banerjee S. Juglone-ascorbic acid synergy inhibits metastasis and induces apoptotic cell death in poorly differentiated thyroid carcinoma by perturbing SOD and catalase activities. Biochem. Mol. Toxicol. (2018) 32: e22176.
  • Wang D, Gao Z and Zhang X. Resveratrol induces apoptosis in murine prostate cancer cells via hypoxia-inducible factor1-alpha (HIF-1α)/reactive oxygen species (ROS)/P53 signalling. Sci. Monit. (2018) 24: 8970–76.
  • Badr El-Din NK, Shabana SM, Abdulmajeed BA and Ghoneum M. A novel kefir product (PFT) inhibits Ehrlich ascites carcinoma in mice via induction of apoptosis and immunomodulation. BMC Complement Med. Ther. (2020) 20: 127.
  • Mamdooh G and James G. Apoptotic effect of a novel kefir product, PFT, on multidrug-resistant myeloid leukemia cells via a hole-piercing mechanism. J. Oncol. (2014) 44: 830–37.
  • Kale J, Osterlund EJ and Andrews DW. BCL-2 family proteins: changing partners in the dance towards death. Cell Death Differ. (2018) 25: 65–80.
  • Saha T, Kar RK and Sa G. Structural and sequential context of p53: A review of experimental and theoretical evidence. Biophys Mol. Biol. (2015) 117: 250–63.
  • He W, Wang Q, Xu J, Xu X, Padilla MT, Ren G, Gou X, Lin Y. Attenuation of TNFSF10/TRAIL induced apoptosis by an autophagic survival pathway involving TRAF2 and RIPK1/RIP1 mediated MAPK8/JNK activation. Autophagy (2012) 8: 1811–21.
  • You M, Savaraj N, Kuo MT, Wangpaichitr M, Varona-Santos J, Wu C, Nguyen DM and Feun L. TRAIL induces autophagic protein cleavage through caspase activation in melanoma cell lines under arginine deprivation. Cell. Biochem. (2013) 374: 181–90.
  • Shakeri R, Kheirollahi A and Davoodi J. Apaf-1: Regulation and function in cell death. Biochimie (2017) 135: 111–25.
  • Mirzapur P, Khazaei MR, Moradi MT and Khazaei M. Apoptosis induction in human breast cancer cell lines by the synergic effect of raloxifene and resveratrol through increasing proapoptotic genes. Life Sci. (2018) 205: 45–53.
  • El-Azab M, Hishe H, Moustafa Y and El-Awady el-S. Anti-angiogenic effect of resveratrol or curcumin in Ehrlich Ascites Carcinoma-bearing mice. J. Pharmacol. (2011) 652(1-3): 7–14.
  • Ourique F, Kviecinski MR, Felipe KB, Correia JF, Farias MS, Castro LS, Grinevicius VM, Valderrama J, Rios D, Benites J, Calderon PB and Pedrosa RC. DNA damage and inhibition of akt pathway in mcf-7 cells and Ehrlich tumor in mice treated with 1,4-naphthoquinones in combination with ascorbate. Med. Cell. Longev. (2015) 2015: 495305.
  • Jin X, Zhang Y, Zhang Z, Che D and Lv H. Juglone loaded poloxamer188/phospholipid mixed micelles evaluated in-vitro and in-vivo in breast cancer. J. Pharm. (2016) 515: 359–66.