Modulation of p53 in 7,12-dimethylbenz[a]anthracene-induced skin tumors by diallyl sulfide in Swiss albino mice.
Allium vegetables have been shown to have beneficial health effects against several chronic diseases including cancer. Diallyl sulfide (DAS), an organosulfur compound present in garlic, is well known for its chemopreventive properties in several tumor models. The pharmacologic role of DAS in prevention and treatment of cancer is well documented in the literature, but its molecular mechanism of action is not yet well defined. In the present study, modulation in p53 expression by topical application of DAS was recorded in 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin tumors in Swiss albino mice. Western blot analysis and immunohistochemical protein detection, combined with multivariable flow cytometry, show that DAS application induces the expression of the wild-type (wt) p53 and down-regulates the expression of mutant (mut) p53. Immunoblotting analysis of tumors showed significant increase in levels of wtp53 by DAS application, whereas for mutp53 the DMBA-induced levels of protein were found to reduce to near normal levels with DAS application. The quantitative analysis of immunostained skin/tumor sections using image analysis and quantitative stereology showed 66.6% and 54.2% increases in wtp53 levels and 53.4% and 44.3% decreases in mutp53 levels in animals where DAS was applied 1 hour prior to or 1 hour after DMBA application, respectively. Flow cytometric analysis further confirmed modulation of wtp53 and mutp53 protein in DAS-supplemented tumors. The increase in the expression of wt tumor suppressor gene protein p53 was accompanied by elevation of the levels of cyclin-dependent kinase inhibitor p21/waf1. The percentage increase in the levels of p21/waf1 was found to be 72.9% and 61.3%, respectively, in DAS-supplemented groups before and after administration. These results thus show that DAS is a potential chemopreventive agent capable of modulating and regulating the tumor suppressor p53 along with its downstream effective molecule, p21/waf1. Thus, DAS can be a potential chemopreventive agent against skin tumor development.
Arora
Annu
A
Environmental Carcinogenesis Division, Industrial Toxicology Research Center, PO Box 80, MG Marg, Lucknow 226001, India.
Siddiqui
Imtiaz A
IA
Shukla
Yogeshwer
Y
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000494:pharmacology*; D000498:Allyl Compounds / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation / Q000235:genetics; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D000498:Allyl Compounds; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D013440:Sulfides; D016159:Tumor Suppressor Protein p53; D015127:9,10-Dimethyl-1,2-benzanthracene; C038491:allyl sulfide