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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."

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