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Journal of Chinese Integrative Medicine ›› 2010, Vol. 8 ›› Issue (7): 645-654.doi: 10.3736/jcim20100708

• Original Experimental Research • Previous Articles     Next Articles

Anti-oncogenic potentials of a plant coumarin (7-hydroxy-6-methoxy coumarin) against 7,12-dimethylbenz[a]anthracene-induced skin papilloma in mice:The possible role of several key signal proteins

Soumya Sundar Bhattacharyyaa,Saili Paula,Suman Duttaa,Naoual Boujedainib,Anisur Rahman Khuda- Bukhsha   

  1. a Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani，Kaslyani 741235, India
    b Boiron Laboratory, 20 rue de la Liberation, Sainte-Les-Foy-Lyon 69110, France
  • Received:2010-01-25 Online:2010-07-20 Published:2018-10-20
  • Contact: Rahman Khuda- Bukhsh Anisur E-mail:khudabukhsh_48@rediffmail.com

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Objective

Anti-cancer potentials of scopoletin (7-hydroxy-6-methoxy coumarin) separated from plant extract (Gelsemium sempervirens) were demonstrated earlier from our in vitro studies. In the present study, its in vivo effects have been evaluated in mice.
Methods

Mice were chronically administered 7,12-dimethylbenz[a]anthracene (DMBA) once a week and croton oil twice a week on their back, which resulted in the development of fully grown finger-like projections (papilloma) after 24 weeks. Two subgroups of mice (drug-treated) were treated with two doses of scopoletin (50 mg and 100 mg/kg body weight) respectively while control received 2% ethyl alcohol (the “vehicle” of scopoletin). After the 24-week drug administration, expressions of several key receptors such as aryl hydrocarbon receptor (AhR) and signal proteins like p53, cytochrome P450 1A1 (CYP1A1), proliferating cell nuclear antigen (PCNA), signal transducer and activator of transcription-3 (Stat-3), survivin, matrix metalloproteinase-2 (MMP-2), cyclin D1, c-myc, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and caspase-3, and some anti-oxidant markers were studied. Lipid peroxidation, superoxide dismutase, catalase, glutathione peroxidase and glutathione-s-transferase in supernatant were also detected.
Results

Carcinogens induced toxicity, and over-expression of AhR, CYP1A1, PCNA, Stat-3, survivin, MMP-2, cyclin D1 and c-myc and down-regulation of p53, caspase-3 and TIMP-2. In mice treated with scopoletin, the expressions of these proteins and toxicity biomarkers were reverted.
Conclusion

Since AhR is known to be ligand-activated by DMBA to release signals for several downstream proteins initiating reactive oxygen species generation, the down-regulation of AhR by scopoletin appeared to play a significant role in subsequent down-regulation of some key signal proteins. One possible mechanism of down-regulation of AhR may be through competitive inhibition by scopoletin. Mitogen-activated protein kinases may also have some critical role. This compound can be considered as a possible candidate for chemoprevention.

Key words: Scopoletin, Skin neoplasms, 7, 12-dimethylbenz[a]anthracene, Signaling receptors, Apoptosis, Mice

Figure 1

Structure of scopoletin"

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Figure 2

Histology of skin tested by haematoxylin and eosin staining and PCNA protein localization Histology of skin: A, B, and C; PCNA localization: D, E, and F. A and D: Normal group; B and E: DMBA plus croton oil group; C and F: Scopoletin-fed group. G: Proportion of average fluorescence intensity of PCNA protein in different groups. **P<0.01, vs DMBA plus alcohol group."

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Figure 3

Immunoblots and mRNA expressions of β-actin, AhR, CYP1A1, Stat-3, p53, PCNA and caspase-3 A: Normal group; B: DMBA plus croton oil group; C: DMBA, croton oil plus alcohol group; D: DMBA, croton oil plus scopoletin (50 mg/kg) group; E: DMBA, croton oil plus scopoletin (100 mg/kg) group."

Figure 4

mRNA expressions and densitometric representation of survivin, cyclin D1, c-myc, MMP-2 and TIMP-2 A: Normal group; B: DMBA plus croton oil group; C: DMBA, croton oil plus alcohol group; D: DMBA, croton oil plus scopoletin (50 mg/kg) group; E: DMBA, croton oil plus scopoletin (100 mg/kg) group."

Figure 5

Immunoblots of expressions of NF-κB and p38MAPK A: Normal group; B: DMBA plus croton oil group; C: DMBA, croton oil plus alcohol group; D: DMBA, croton oil plus scopoletin (50 mg/kg) group; E: DMBA, croton oil plus scopoletin (100 mg/kg) group."

Figure 6

Immunoprecipitation of ARNT blots A: Normal group; B: DMBA plus croton oil group; C: DMBA, croton oil plus alcohol group; D: DMBA, croton oil plus scopoletin (50 mg/kg) group; E: DMBA, croton oil plus scopoletin (100 mg/kg) group."

[1] Kawaii S, Tomono Y, Ogawa K, Sugiura M, Yano M, Yoshizawa Y . The antiproliferative effect of coumarins on several cancer cell lines[J]. Anticancer Res, 2001,21(2A):917-923
[2] Bhattacharyya SS, Mandal SK, Biswas R, Paul S, Pathak S, Boujaedaini N, Belon P, Khuda-Bukhsh AR . In vitro studies demonstrate anticancer activity of an alkaloid of plant Gelsemium semipervirens[J]. Exp Biol Med (Maywood), 2008,233(12):1591-1601
doi: 10.3181/0805-RM-181
[3] Bhattacharyya SS, Paul S, Mondal SK, Banerjee A, Boujedaini N, Khuda-Bukhsh AR . A synthetic coumarin(4-methyl-7-hydroxy coumarin) has anti-cancer potentials against DMBA-induced skin cancer in mice[J]. Eur J Pharmacol, 2009,614(1-3):128-136
doi: 10.1016/j.ejphar.2009.04.015
[4] Takayama H, Sakai SI. Gelsemium alkaloids. In: Cordell GA. The alkaloids(Vol 49)[M]. San Diego, California: Academic Press, 1997,( Vol 49):1-78
[5] Evans WC.Trease and Evans pharmacognosy(15th ed)[M].Philadelphia: WB Saunders,2002,(15th ed)
[6] Das RK, Hossain SK, Bhattacharya S . Diphenylmethyl selenocyanate inhibits DMBA-croton oil induced two-stage skin carcinogenesis by inducing apoptosis and inhibiting cutaneous cell proliferation[J]. Cancer Lett, 2005,230(1):90-101
doi: 10.1016/j.canlet.2004.12.021
[7] Katiyar SK, Roy AM, Baliga MS . Silymarin induces apoptosis primarily through a p53-dependent pathway involving Bcl-2/Bax, cytochrome c release and caspase activation[J]. Mol Cancer Ther, 2005,4(2):207-216
[8] Motiwale L, Ingle AD, Rao KV . Mouse skin tumor promotion by sodium arsenate is associated with enhanced PCNA expression[J]. Cancer Lett, 2005,223(1):27-35
doi: 10.1016/j.canlet.2004.10.020 pmid: 15890234
[9] Limtrakul P, Anuchareeda S, Lipigorngoson S, Dunn FW . Inhibition of carcinogen induced c-Ha-ras and c-fos proto-oncogenes expression by dietary curcumin[J]. BMC Cancer, 2001,1(1):1-7
doi: 10.1186/1471-2407-1-1
[10] Yokozawa T, Chen CP, Dong E, Tanaka T, Nonaka GI, Nishioka I . Study on the inhibitory effect of tannins and flavonoids against the 1,1-diphenyl-2-picrylhydrazyl radical[J]. Biochem Pharmacol, 1998,56(2):213-222
doi: 10.1016/S0006-2952(98)00128-2
[11] Sreejayan N, Rao MNA . Nitric oxide scavenging by curcuminioids[J]. J Pharm Pharmacol, 1997,49(1):105-107
doi: 10.1111/j.2042-7158.1997.tb06761.x pmid: 9120760
[12] Mary NK, Shylesh BS, Babu BH, Padikkala J . Antioxidant and hypolipidaemic activity of a herbal formulation — liposem[J]. Ind J Exp Biol, 2002,40(8):901-904
pmid: 12597019
[13] Currier N, Solomon SE, Demicco EG, Chang DL, Farago M, Ying H, Dominguez I, Sonenshein GE, Cardiff RD, Xiao ZX, Sherr DH, Seldin DC . Oncogenic signaling pathways activated in DMBA-induced mouse mammary tumors[J]. Toxicol Pathol, 2005,33(6):726-737
doi: 10.1080/01926230500352226
[14] Ohkawa H, Ohishi N, Yagi K . Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction[J]. Anal Biochem, 1979,95(2):351-358
doi: 10.1016/0003-2697(79)90738-3 pmid: 36810
[15] Kakkar P, Das B, Viswanathan PN . A modified spectrophotometric assay of superoxide dismutase[J]. Indian J Biochem Biophys, 1984,21(2):130-132
doi: 10.1515/bchm2.1984.365.2.1489 pmid: 6490072
[16] Maehly AC, Chance B.The assay of catalase and peroxidase[J].Methods Biochem Anal , 1954, 1: 357-424
doi: 10.1002/9780470110171.ch14
[17] Paglia DE, Valentine WN . Studies on the quantitative and qualitative characterisation of erythrocyte glutathione peroxidase[J]. J Lab Clin Med, 1967,70(1):158-169
[18] Habig WH, Pabst MJ, Jakoby WB . Glutathione-S-transferase, the first enzymatic step in mercapturic acid formation[J]. J Biol Chem, 1974,249(22):7130-7139
[19] Arabzadeh A, Troy TC , Turksen K.Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis[J].BMC Cancer, 2007, 7: 196
doi: 10.1186/1471-2407-7-196
[20] Burnette WN . “Western blotting”: electrophoretic transfer of proteins from sodium dodecyl sulfate -polyacrylamide gels to unmodified nitrocellulose and radiographic detection with antibody and radioiodinated protein A[J]. Anal Biochem, 1981,112(2):195-203
doi: 10.1016/0003-2697(81)90281-5
[21] Symonds H, Krall L, Remington L, Saenz-Robles M, Lowe S, Jacks T , Van Dyke T.p53-dependent apoptosis suppresses tumor growth and progression in vivo[J]. Cell, 1994,78(4):703-711
doi: 10.1016/0092-8674(94)90534-7 pmid: 8069917
[22] Lowe SW, Jacks T, Housman DE, Ruley HE . Abrogation of oncogene-associated apoptosis allows transformation of p53-deficient cells[J]. Proc Natl Acad Sci, 1994,91(6):2026-2030
doi: 10.1016/j.ajpath.2012.08.025 pmid: 8134344
[23] Donehower LA, Harvey M, Slagle BL , McArthur MJ, Montgomery CA Jr, Butel JS, Bradley A.Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumors[J]. Nature, 1992,356(6366):215-221
doi: 10.1038/356215a0 pmid: 1552940
[24] Hollstein M, Rice K, Greenblatt MS, Soussi T, Fuchs R, Sorlie T, Hovig E, Smith-Shorensen B, Montesano R, Harris CC . Database of p53 gene somatic mutations in human tumors and cell lines[J]. Nucleic Acids Res, 1994,22(17):3551-3555
[25] Venkatarachalam S, Shi YP, Jones SN, Vogel H, Bradley A, Pinkel D, Donehower LA . Retention of wild-type p53 in tumors from p53 heterozygous mice: reduction of p53 dosage can promote cancer formation[J]. EMBO J, 1998,17(16):4657-4667
doi: 10.1093/emboj/17.16.4657
[26] Li FZ, Brattain MG . Role of the survivin gene in pathophysiology[J]. Am J Pathol, 2006,169(1):1-11
doi: 10.2353/ajpath.2006.060121 pmid: 16816356
[27] Singhal R, Badger TM, Ronis MJ . Reduction in 7,12-dimethylbenz[a]anthracene-induced hepatic cytochrome-P450 1A1 expression following soy consumption in female rats is mediated by degradation of Aryl hydrocarbon receptor[J]. J Nutr, 2007,137(1):19-24
doi: 10.1093/jn/137.1.19
[28] Jung KJ, Wallig MA, Singletary KW . Purple grape juice inhibits 7,12-dimethylbenz[a]antracene(DMBA)-induced rat mammary tumorigenesis and in vivo DMBA-DNA adduct formation[J]. Cancer Lett, 2006,233(2):279-288
doi: 10.1016/j.canlet.2005.03.020
[29] Lee BC, Lee SY, Lee HJ, Sim GS, Kim JH, Kim JH, Cho YH, Lee DH, Pyo HB, Choe TB, Moon DC, Yun YP, Hong JT . Anti-oxidative and photo-protective effects of coumarins isolated from Fraxinus Chinensis[J]. Arch Pharm Res, 2007,30(10):1293-1301
doi: 10.1007/BF02980270
[30] Kim SO, Kundu JK, Shin YK, Park JH, Cho MH, Kim TY, Surh YJ .[ 6]-Gingerol inhibits COX-2 expression by blocking the activation of p38 MAP kinase and NF-kappaB in phorbol ester-stimulated mouse skin[J]. Oncogene, 2005,24(15):2558-2567
doi: 10.1038/sj.onc.1208446
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