Anti-proliferative and apoptotic efficacy of diallyl disulfide on Ehrlich ascites carcinoma

Abstract

Aim: This study was conducted to assess the in vivo and in vitro anti-tumor effects of diallyl disulfide (DADS) against Ehrlich ascites carcinoma (EAC) and to suggest its probable mechanism of action.

Methods: EAC was induced in female mice by intraperitoneal injection of EAC-cells from stock mice. EAC-bearing mice were orally treated with 100 mg/kg body weight for 2 weeks beginning from the 1st day of EAC intraperitoneal transplantation. Cytotoxicity effects of DADS against EAC-cells in vitro were investigated at different concentrations (0, 6.25, 12.5, 25, 50, and 100 μg/mL) of DADS using trypan blue exclusion assay.

Results: Data from this study exhibited a significant decrease in EAC-aliquot volume as well as total and alive EAC-cell number and a marked increase in dead EAC-cell number and percent in EAC-bearing mice treated with DADS as compared with EAC-bearing control. These changes were consistent with increased number of cells which exhibited phenotypic apoptotic signs marked by a decrease in the expression of anti-apoptotic protein Bcl-2, an increase of pro-apoptotic and cell cycle arrest mediator p53 and an elevation of DNA fragmenting indicator terminal deoxynucleotidyl transferase in EAC-bearing mice treated with DADS. In addition, the tumor marker sialic acid level was markedly decreased in plasma and Ehrlich ascites in EAC-bearing mice treated with DADS. In vitro, DADS also produced anti-proliferative and anti-tumor cytotoxic potentials against EAC.

Conclusion: DADS may have anti-cancer effects which may be mediated via modulation of apoptosis and cell cycle arrest.

Keywords

Anti-proliferative effects / apoptosis / diallyl disulfide / Ehrlich ascites carcinoma / imaging / semi-quantitative analysis

References

[1] Bilecová-Rabajdová M,Urban P,Durovcová E.Naturally occurring substances and their role in chemo-protective effects..Cent Eur J Public Health2013;21:213-9

[2] Jo HJ,Kim KM,Kim KH.Diallyl disulfide induces reversible G2/M phase arrest on a p53-independent mechanism in human colon cancer HCT-116 cells..Oncol Rep2008;19:275-80

[3] Thakur VS,Babcook MA.Plant phytochemicals as epigenetic modulators: role in cancer chemoprevention..AAPS J2014;16:151-63 PMCID:PMC3889536

[4] Le Bon AM.Organosulfur compounds from Allium and the chemoprevention of cancer..Drug Metabol Drug Interact2000;17:51-79

[5] Thomson M.Garlic [Allium sativum]: a review of its potential use as an anti-cancer agent..Curr Cancer Drug Targets2003;3:67-81

[6] Wen J,Chen X,Li GC.Enhancement of diallyl disulfide-induced apoptosis by inhibitors of MAPKs in human HepG2 hepatoma cells..Biochem Pharmacol2004;68:323-31

[7] Herman-Antosiewicz A.Signal transduction pathways leading to cell cycle arrest and apoptosis induction in cancer cells by Allium vegetable-derived organosulfur compounds: a review..Mutat Res2004;555:121-31

[8] Belloir C,Daurat C,Le Bon AM.Protective effects of garlic sulfur compounds against DNA damage induced by direct- and indirect-acting genotoxic agents in HepG2 cells..Food Chem Toxicol2006;44:827-34

[9] Fleischauer AT.Garlic and cancer: a critical review of the epidemiologic literature..J Nutr2001;131:S1032-40

[10] Bottone FGJr,Nixon JB.Diallyl disulfide (DADS) induces the antitumorigenic NSAID-activated gene (NAG-1) by a p53-dependent mechanism in human colorectal HCT 116 cells..J Nutr2002;132:773-8

[11] Xiang SL,Ling H,Zhou XT,Su Q.Antitumor effect of diallyl disulfide on human gastric cancer MGC803 cells xenograft in nude mice..Ai Zheng2005;24:940-4

[12] Yuan XK,Jiang XY.Synthesis, characterization and bioactivity of diallyl disulphide..J Cent S Univ Technol2006;13:515-8

[13] Freshney RI.Culture of Animal Cells: a Manual of Basic Technique.3rd ed. New York: Wiley;1994;

[14] Freitas ES,Silva AE,Ferreira E,Cassali GD.Effect of thyroxine and propylthiouracil in Ehrlish asitic tumor cells..Int J Morphol2006;24:665-71

[15] Chandru H,Bettadaiah BK,Rangappa KS,Jayashree K.In vivo growth inhibitory and anti-angiogenic effects of synthetic novel dienone cyclopropoxy curcumin analogs on mouse Ehrlich ascites tumor..Bioorg Med Chem2007;15:7696-703

[16] Warren L.The thiobarbituric acid assay of sialic acids..J Biol Chem1959;234:1971-5

[17] Negoescu A,Labat-Moleur F,Robert C,Brambilla C.In situ apoptotic cell labeling by the TUNEL method: improvement and evaluation on cell preparations..J Histochem Cytochem1996;44:959-68

[18] Gao H.Inhibitory effect of picroside II on hepatocyte apoptosis..Acta Pharmacol Sin2005;26:729-36

[19] Ahmed OM.Anti-proliferative and apoptotic efficacies of ulvan polysaccharides against different types of carcinoma cells in vitro and in vivo..J Cancer Sci Ther2014;6:202-8

[20] Rao M,Zonneberg M.PC-STAT programs, version 1A (C), one and two way analysis of variance.Athens, GA: The University of Georgia;1985;

[21] Arican G.Evaluation of the apoptotic and anti-proliferative activities of paclitaxel in Ehrlish ascites tumor cells..Biotechnol Biotechnol Equip2006;20:69-75

[22] Ozen N,Ozen M,Altug T,Kokoglu E.Curcumin's effects on sialic acid level and sialidase activity in Ehrlich ascites tumor bearing mice..Tohoku J Exp Med2002;197:221-7

[23] Kuttan G.Effect of diallyl sulphide, diallyl disulphide, and allyl methyl sulphide on the inhibition of lung metastasis of B16F-10 melanoma cells in mice..J Clin Biochem Nutr1999;27:131-9

[24] Vijay V,Raiker VG.Effect of diallyl disulphide on renal glycated proteins and plasma sialic acid levels in alloxan diabetic rats..Glob J Med Res2011;11:31-5

[25] Gunadharini DN,Krishnamoorthy G,Vijayababu MR,Srinivasan N,Arunakaran J.Antiproliferative effect of diallyl disulfide (DADS) on prostate cancer cell line LNCaP..Cell Biochem Funct2006;24:407-12

[26] Sriram N,Ashokkumar P,Sudhandiran G.Diallyl sulfide induces apoptosis in Colo 320 DM human colon cancer cells: involvement of caspase-3, NF-kappaB, and ERK-2..Mol Cell Biochem2008;311:157-65

[27] Mondal S,Ghosh MK,Roy S.Natural products: promising resources for cancer drug discovery..Anticancer Agents Med Chem2012;12:49-75

[28] Bhattacharyya A,Pal S,Datta GK,Das T.Apoptogenic effects of black tea on Ehrlich's ascites carcinoma cell..Carcinogenesis2003;24:75-80

[29] Hussein AM.Regioselective one-pot synthesis and anti-proliferative and apoptotic effects of some novel tetrazolo[1,5-a] pyrimidine derivatives..Bioorg Med Chem2010;18:2639-44

[30] Meng LH,Hayward L,Shao RG.Tetrandrine induces early G1 arrest in human colon carcinoma cells by down-regulating the activity and inducing the degradation of G1-S-specific cyclin-dependent kinases and by inducing p53 and p21Cip1..Cancer Res2004;64:9086-92

[31] Chen Y,Zhao WM.The p53 pathway is synergized by p38 MAPK signaling to mediate 11,11'-dideoxyverticillin-induced G2/M arrest..FEBS Lett2005;579:3683-90

[32] Ianzini F,Kosmacek EA,Mackey MA.Lack of p53 function promotes radiation-induced mitotic catastrophe in mouse embryonic fibroblast cells..Cancer Cell Int2006;6:11 PMCID:PMC1479380

[33] Ahmed OM,Ahmed RR.Synthesis and anti-tumor activities of some new pyridines and pyrazolo[1,5-a] pyrimidines..Eur J Med Chem2009;44:3519-23

[34] Deng Y.Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria..Proc Natl Acad Sci U S A2000;97:12050-5 PMCID:PMC17292

[35] Knowles LM.Possible mechanism by which allyl sulfides suppress neoplastic cell proliferation..J Nutr2001;131:S1061-6

[36] Robert V,Mayeur C,Blachier F.Effects of the garlic compound diallyl disulfide on the metabolism, adherence and cell cycle of HT-29 colon carcinoma cells: evidence of sensitive and resistant sub-populations..Carcinogenesis2001;22:1155-61

[37] Oommen S,Srinivas G.Allicin (from garlic) induces caspase-mediated apoptosis in cancer cells..Eur J Pharmacol2004;485:97-103

[38] Folkman J.Tumor angiogenesis: therapeutic implications..N Engl J Med1971;285:1182-6

[39] Risau W.Mechanisms of angiogenesis..Nature1997;386:671-4

[40] Bergers G.Tumorigenesis and the angiogenic switch..Nat Rev Cancer2003;3:401-10

[41] Senger DR,Dvorak AM,Harvey VS.Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid..Science1983;219:983-5

[42] Funasaka T,Raz A.Tumor autocrine motility factor induces hyperpermeability of endothelial and mesothelial cells leading to accumulation of ascites fluid..Biochem Biophys Res Commun2002;293:192-200

[43] Iciek MB,Wlodek LB.Effects of diallyl disulfide and other donors of sulfane sulfur on the proliferation of human hepatoma cell line (HepG2)..Neoplasma2001;48:307-12

[44] De Martino A,Aquilano K,Rotilio G.Effects of water garlic extracts on cell cycle and viability of HepG2 hepatoma cells..J Nutr Biochem2006;17:742-9

[45] Ahmed OM,Mossa NM.Chemopreventive effect of diallyl disulphide on CCl -induced liver injury in albino rats..J Egypt Ger Soc Zool2008;56A:25-62

[46] Abdel-Aleem SR,Mossa NM.Chemopreventive effects of diallyl disulphide on CCl -induced kidney injury and haematological disturbances in albino rats..J Egypt Ger Soc Zool2007;55C:389-419

[47] García A,Arranz N,Rafter J.Organosulfur compounds alone or in combination with vitamin C protect towards N-nitrosopiperidine- and N-nitrosodibutylamine-induced oxidative DNAdamage in HepG2 cells..Chem Biol Interact2008;173:9-18