![conference banner](/images/conference-banner.jpeg)
Abstract
Background: Development of effective cancer-chemotherapy is the most challenging field due to the toxicity of chemo-agents.
Objective: As chalcone has been known to have pharmacological applications, here the aim is to synthesized three chalcone derivatives, 2',4'-dihydroxy-3,4-methylenedioxychalcone (C1), 2'-hydroxy- 2,4, 6-trimethoxychalcone (C2) and 2'-hydroxy-4-methylchalcone (C3) and investigate their anti-cancer properties against Ehrlich Ascites Carcinoma (EAC) cell. Methods: Anticancer properties against EAC cells were studied by examining growth inhibition, MTT assays, tumour-bearing mice survival, tumour weight measurement and haematological profiles. Moreover, apoptosis of EAC cells was investigated by fluorescence microscopy, flowcytometry and DNA fragmentation assays. Expression of apoptosis related genes were studied by reverse transcriptase-PCR (RT-PCR). Results: Among the compounds, C1 exhibited highest cell growth inhibition at 200 mg/kg/day (81.71%; P < 0.01). C1 treatment also increased the life span of EAC-bearing mice (82.60%, P < 0.05) with the reduction of tumour burden (22.2%, P < 0.01) compared to untreated EAC-bearing mice. In vitro study indicated that C1 killed EAC-cells in a dose-dependent manner and induced mitochondria-mediated apoptotic pathways. In addition, C1 treated cells exhibited increased apoptotic features such as membrane blebbing, chromatin condensation, and nuclear fragmentation after Hoechst 33342 staining. Increased fragmentation of DNA in gel electrophoresis followed by C1 treatment further confirmed apoptosis of EAC cells. EAC cells treated with C1 showed reduced Bcl-2 expression in contrast to notable upregulation of p53 and Bax expression. It implied that C1 could reinstate the expression of pro-apoptotic tumour suppressor and inhibit anti-apoptotic genes. Conclusions: Thus, C1 showed significant growth inhibitory properties and induced apoptosis of EAC cells.Keywords: Apoptosis, host toxicity, EAC cells, chalcones, survival time, tumour growth.
[1]
Di Carlo G, Mascolo N, Izzo AA, Capasso F. Flavonoids: old and new aspects of a class of natural therapeutic drugs. Life Sci 1999; 65(4): 337-53.
[http://dx.doi.org/10.1016/S0024-3205(99)00120-4] [PMID: 10421421]
[http://dx.doi.org/10.1016/S0024-3205(99)00120-4] [PMID: 10421421]
[2]
Go ML, Wu X, Liu XL. Chalcones: an update on cytotoxic and chemoprotective properties. Curr Med Chem 2005; 12(4): 481-99.
[http://dx.doi.org/10.2174/0929867053363153] [PMID: 15720256]
[http://dx.doi.org/10.2174/0929867053363153] [PMID: 15720256]
[3]
Echeverria C, Santibañez JF, Donoso-Tauda O, Escobar CA, Ramirez-Tagle R. Structural antitumoral activity relationships of synthetic chalcones. Int J Mol Sci 2009; 10(1): 221-31.
[http://dx.doi.org/10.3390/ijms10010221] [PMID: 19333443]
[http://dx.doi.org/10.3390/ijms10010221] [PMID: 19333443]
[4]
Nowakowska Z. A review of anti-infective and anti-inflammatory chalcones. Eur J Med Chem 2007; 42(2): 125-37.
[http://dx.doi.org/10.1016/j.ejmech.2006.09.019] [PMID: 17112640]
[http://dx.doi.org/10.1016/j.ejmech.2006.09.019] [PMID: 17112640]
[5]
Hsieh HK, Tsao LT, Wang JP, Lin CN. Synthesis and anti-inflammatory effect of chalcones. J Pharm Pharmacol 2000; 52(2): 163-71.
[http://dx.doi.org/10.1211/0022357001773814] [PMID: 10714946]
[http://dx.doi.org/10.1211/0022357001773814] [PMID: 10714946]
[6]
Viana GS, Bandeira MA, Matos FJ. Analgesic and antiinflammatory effects of chalcones isolated from Myracrodruon urundeuva allemão. Phytomedicine 2003; 10(2-3): 189-95.
[http://dx.doi.org/10.1078/094471103321659924] [PMID: 12725575]
[http://dx.doi.org/10.1078/094471103321659924] [PMID: 12725575]
[7]
Zhao LM, Jin HS, Sun LP, Piao HR, Quan ZS. Synthesis and evaluation of antiplatelet activity of trihydroxychalcone derivatives. Bioorg Med Chem Lett 2005; 15(22): 5027-9.
[http://dx.doi.org/10.1016/j.bmcl.2005.08.039] [PMID: 16169724]
[http://dx.doi.org/10.1016/j.bmcl.2005.08.039] [PMID: 16169724]
[8]
Murakami S, Kijima H, Isobe Y, et al. Inhibition of gastric H+, K(+)-ATPase by chalcone derivatives, xanthoangelol and 4-hydroxyderricin, from Angelica keiskei Koidzumi. J Pharm Pharmacol 1990; 42(10): 723-6.
[http://dx.doi.org/10.1111/j.2042-7158.1990.tb06568.x] [PMID: 1982146]
[http://dx.doi.org/10.1111/j.2042-7158.1990.tb06568.x] [PMID: 1982146]
[9]
Singh P, Anand A, Kumar V. Recent developments in biological activities of chalcones: A mini review. Eur J Med Chem 2014; 85: 758-77.
[10]
Szliszka E, Czuba ZP, Mazur B, Sedek L, Paradysz A, Krol W. Chalcones enhance TRAIL-induced apoptosis in prostate cancer cells. Int J Mol Sci 2009; 11(1): 1-13.
[http://dx.doi.org/10.3390/ijms11010001] [PMID: 20161998]
[http://dx.doi.org/10.3390/ijms11010001] [PMID: 20161998]
[11]
Andreani A, Granaiola M, Locatelli A, et al. Cytotoxic activities of substituted 3-(3,4,5-trimethoxybenzylidene)-1,3-dihydroindol-2-ones and studies on their mechanisms of action. Eur J Med Chem 2013; 64: 603-12.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.033] [PMID: 23685944]
[http://dx.doi.org/10.1016/j.ejmech.2013.03.033] [PMID: 23685944]
[12]
Sharma A, Chakravarti B, Gupt MP, Siddiqui JA, Konwar R, Tripathi RP. Synthesis and anti breast cancer activity of biphenyl based chalcones. Bioorg Med Chem 2010; 18(13): 4711-20.
[http://dx.doi.org/10.1016/j.bmc.2010.05.015] [PMID: 20605470]
[http://dx.doi.org/10.1016/j.bmc.2010.05.015] [PMID: 20605470]
[13]
Zheng X, Zhao FF, Liu YM, et al. Synthesis and preliminary biological evaluation of chrysin derivatives as potential anticancer drugs. Med Chem 2010; 6(1): 6-8.
[http://dx.doi.org/10.2174/157340610791208763] [PMID: 20402655]
[http://dx.doi.org/10.2174/157340610791208763] [PMID: 20402655]
[14]
Echevarriaa A, da Graça-Nascimentob M, Gerônimob V, Millerc J, Giesbrechtd A. NMR spectroscopy, hammett corre-lations and biological activity of some Schiff bases derived from piperonal. J Braz Chem Soc 1999; 10: 60-4.
[http://dx.doi.org/10.1590/S0103-50531999000100010]
[http://dx.doi.org/10.1590/S0103-50531999000100010]
[15]
Syam S, Abdelwahab SI, Al-Mamary MA, Mohan S. Synthesis of chalcones with anticancer activities. Molecules 2012; 17(6): 6179-95.
[http://dx.doi.org/10.3390/molecules17066179] [PMID: 22634834]
[http://dx.doi.org/10.3390/molecules17066179] [PMID: 22634834]
[16]
Sporn MB, Liby KT. Cancer chemoprevention: scientific promise, clinical uncertainty. Nat Clin Pract Oncol 2005; 2(10): 518-25.
[http://dx.doi.org/10.1038/ncponc0319] [PMID: 16205771]
[http://dx.doi.org/10.1038/ncponc0319] [PMID: 16205771]
[17]
Kostanecki SV, Tambor J. Ueber die sechs isomeren monooxybenzalacetophenone (Monooxychalkone). Ber Dtsch Chem Ges 1899; 32: 1921-6.
[http://dx.doi.org/10.1002/cber.18990320293]
[http://dx.doi.org/10.1002/cber.18990320293]
[18]
Islam F, Ali SM, Khanam JA. Hepatoprotective effect of acetone semicarbazone on Ehrlich ascites carcinoma induced carcinogenesis in experimental mice. Asian Pac J Trop Biomed 2013; 3(2): 105-10.
[http://dx.doi.org/10.1016/S2221-1691(13)60033-7] [PMID: 23593588]
[http://dx.doi.org/10.1016/S2221-1691(13)60033-7] [PMID: 23593588]
[19]
Islam F, Ghosh S, Khanam JA. Antiproliferative and hepatoprotective activity of metabolites from Corynebacterium xerosis against Ehrlich Ascites Carcinoma cells. Asian Pac J Trop Biomed 2014; 4(Suppl. 1): S284-92.
[http://dx.doi.org/10.12980/APJTB.4.2014C1283] [PMID: 25183099]
[http://dx.doi.org/10.12980/APJTB.4.2014C1283] [PMID: 25183099]
[20]
Khanam JA, Islam MF, Jesmin M, Ali MM. Antineoplastic activity of Acetone Semicarbazone (ASC) against Ehrlich Asci-tes Carcinoma (EAC) bearing mice. J Natl Sci Found Sri Lanka 2010; 38: 225-31.
[http://dx.doi.org/10.4038/jnsfsr.v38i4.2649]
[http://dx.doi.org/10.4038/jnsfsr.v38i4.2649]
[21]
Islam F, Khanam JA, Khatun M, et al. A p-menth-1-ene-4,7-diol (EC-1) from Eucalyptus camaldulensis Dhnh. triggers apoptosis and cell cycle changes in Ehrlich ascites carcinoma cells. Phytother Res 2015; 29(4): 573-81.
[http://dx.doi.org/10.1002/ptr.5288] [PMID: 25583285]
[http://dx.doi.org/10.1002/ptr.5288] [PMID: 25583285]
[22]
Islam F, Khatun H, Khatun M, Ali SM, Khanam JA. Growth inhibition and apoptosis of Ehrlich ascites carcinoma cells by the methanol extract of Eucalyptus camaldulensis. Pharm Biol 2014; 52(3): 281-90.
[http://dx.doi.org/10.3109/13880209.2013.834365] [PMID: 24102623]
[http://dx.doi.org/10.3109/13880209.2013.834365] [PMID: 24102623]
[23]
Kabir SR, Hossen A, Zubair A, et al. A new lectin from the tuberous rhizome of Kaempferia rotunda: isolation, characterization, antibacterial and antiproliferative activities. Protein Pept Lett 2011; 18(11): 1140-9.
[http://dx.doi.org/10.2174/092986611797200896] [PMID: 21707523]
[http://dx.doi.org/10.2174/092986611797200896] [PMID: 21707523]
[25]
Orlikova B, Tasdemir D, Golais F, Dicato M, Diederich M. Dietary chalcones with chemopreventive and chemotherapeutic potential. Genes Nutr 2011; 6(2): 125-47.
[http://dx.doi.org/10.1007/s12263-011-0210-5] [PMID: 21484163]
[http://dx.doi.org/10.1007/s12263-011-0210-5] [PMID: 21484163]
[26]
Sharma V, Kumar V, Kumar P. Heterocyclic chalcone analogues as potential anticancer agents. Anticancer Agents Med Chem 2013; 13(3): 422-32.
[PMID: 22721390]
[PMID: 22721390]
[27]
Wan M, Xu L, Hua L, et al. Synthesis and evaluation of novel isoxazolyl chalcones as potential anticancer agents. Bioorg Chem 2014; 54: 38-43.
[http://dx.doi.org/10.1016/j.bioorg.2014.03.004] [PMID: 24747188]
[http://dx.doi.org/10.1016/j.bioorg.2014.03.004] [PMID: 24747188]
[28]
Ethiraj KR, Aranjani JM, Khan FR. Synthesis of methoxy-substituted chalcones and in vitro evaluation of their anticancer potential. Chem Biol Drug Des 2013; 82(6): 732-42.
[http://dx.doi.org/10.1111/cbdd.12184] [PMID: 23834620]
[http://dx.doi.org/10.1111/cbdd.12184] [PMID: 23834620]
[29]
Kopp F, Hermawan A, Oak PS, Herrmann A, Wagner E, Roidl A. Salinomycin treatment reduces metastatic tumor burden by hampering cancer cell migration. Mol Cancer 2014; 13: 16.
[http://dx.doi.org/10.1186/1476-4598-13-16] [PMID: 24468090]
[http://dx.doi.org/10.1186/1476-4598-13-16] [PMID: 24468090]
[30]
Livshits Z, Rao RB, Smith SW. An approach to chemotherapy-associated toxicity. Emerg Med Clin North Am 2014; 32(1): 167-203.
[http://dx.doi.org/10.1016/j.emc.2013.09.002] [PMID: 24275174]
[http://dx.doi.org/10.1016/j.emc.2013.09.002] [PMID: 24275174]
[31]
Clarkson BD, Buirchena JH. Preliminary screening of anti-cancer drugs. Prog Clin Cancer 1965; 1: 625-9.
[PMID: 14283934]
[PMID: 14283934]
[33]
Kabir SR, Islam MF, Alom MJ, Abu Zubair M, Absar N. Purification, characterizations of a snake guard seeds lectin with antitumor activity against Ehrlich ascites carcinoma cells in vivo in mice. Protein Pept Lett 2012; 19(3): 360-8.
[http://dx.doi.org/10.2174/092986612799363154] [PMID: 22185504]
[http://dx.doi.org/10.2174/092986612799363154] [PMID: 22185504]
[34]
Perveen R, Islam F, Khanum J, Yeasmin T. Preventive effect of ethanol extract of Alpinia calcarata Rosc on Ehrlich’s ascitic carcinoma cell induced malignant ascites in mice. Asian Pac J Trop Med 2012; 5(2): 121-5.
[http://dx.doi.org/10.1016/S1995-7645(12)60009-1] [PMID: 22221755]
[http://dx.doi.org/10.1016/S1995-7645(12)60009-1] [PMID: 22221755]
[35]
Ye CL, Qian F, Wei DZ, Lu YH, Liu JW. Induction of apoptosis in K562 human leukemia cells by 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone. Leuk Res 2005; 29(8): 887-92.
[http://dx.doi.org/10.1016/j.leukres.2005.01.006] [PMID: 15978939]
[http://dx.doi.org/10.1016/j.leukres.2005.01.006] [PMID: 15978939]
[36]
Chang HJ, Yoon G, Park JS, et al. Induction of apoptosis by the licochalcone E in endothelial cells via modulation of NF-kappaB and Bcl-2 Family. Biol Pharm Bull 2007; 30(12): 2290-3.
[http://dx.doi.org/10.1248/bpb.30.2290] [PMID: 18057714]
[http://dx.doi.org/10.1248/bpb.30.2290] [PMID: 18057714]
[37]
Lou C, Wang M, Yang G, et al. Preliminary studies on anti-tumor activity of 2′,4′-dihydroxychalcone isolated from Herba Oxytropis in human gastric cancer MGC-803 cells. Toxicol In Vitro 2009; 23(5): 906-10.
[http://dx.doi.org/10.1016/j.tiv.2009.05.002] [PMID: 19457454]
[http://dx.doi.org/10.1016/j.tiv.2009.05.002] [PMID: 19457454]
[38]
Jiang CP, Ding H, Shi DH, Wang YR, Li EG, Wu JH. Pro-apoptotic effects of tectorigenin on human hepatocellular carcinoma HepG2 cells. World J Gastroenterol 2012; 18(15): 1753-64.
[http://dx.doi.org/10.3748/wjg.v18.i15.1753] [PMID: 22553399]
[http://dx.doi.org/10.3748/wjg.v18.i15.1753] [PMID: 22553399]
[39]
Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 2008; 19(3-4): 325-31.
[http://dx.doi.org/10.1016/j.cytogfr.2008.04.001] [PMID: 18495520]
[http://dx.doi.org/10.1016/j.cytogfr.2008.04.001] [PMID: 18495520]
[40]
Ma ZY, Qiao X, Xie CZ, et al. Activities of a novel Schiff base copper(II) complex on growth inhibition and apoptosis induction toward MCF-7 human breast cancer cells via mitochondrial pathway. J Inorg Biochem 2012; 117: 1-9.
[http://dx.doi.org/10.1016/j.jinorgbio.2012.08.007] [PMID: 23073509]
[http://dx.doi.org/10.1016/j.jinorgbio.2012.08.007] [PMID: 23073509]
[41]
Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin 2005; 55(3): 178-94.
[http://dx.doi.org/10.3322/canjclin.55.3.178] [PMID: 15890640]
[http://dx.doi.org/10.3322/canjclin.55.3.178] [PMID: 15890640]
Article Metrics
![Wayfinder Image](/images/wayfinder.jpg)