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.
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.


CONCLUSIONS
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.
Bhattacharyya
Soumya Sundar
SS
Cytogenetics and Molecular Biology Laboratory, Department of Zoology, University of Kalyani, Kalyani 741235, India.
Paul
Saili
S
Dutta
Suman
S
Boujedaini
Naoual
N
Khuda-Bukhsh
Anisur Rahman
AR
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010212:Papilloma / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D008517:Phytotherapy; D012603:Scopoletin / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D019716:Tissue Inhibitor of Metalloproteinase-2; D015127:9,10-Dimethyl-1,2-benzanthracene; D020928:Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020778:Matrix Metalloproteinase 2; C522362:Mmp2 protein, mouse; D012603:Scopoletin