Chemopreventative strategies targeting the MGMT repair protein: Augmented expression in human lymphocytes and tumor cells by ethanolic and aqueous extracts of several Indian medicinal plants

Abstract

O6-alkylguanines are potent mutagenic, procarcinogenic and cytotoxic lesions induced by exogenous and endogenous alkylating agents. A facilitated elimination of these lesions by increasing the activity of O 6-methylguanine-DNA methyltransferase (MGMT) is likely to be a beneficial chemoprevention strategy, which, however, has not been examined. Because, a marginal enhancement of this protein may be adequate for genomic protection, we studied alterations in MGMT activity and expression in human peripheral blood lymphocytes and cancer cell lines induced by water-soluble and alcohol-soluble constituents of several plants with established antioxidant and medicinal properties. Both the ethanolic and aqueous extracts from neem (Azadirachta indica), holy basil (Ocimum sanctum), winter cherry (Withania somnifera), and oregano (Origanum majorana) increased the levels of MGMT protein and its demethylation activity in a time-dependent manner with a maximum of 3-fold increase after 72-h treatment. The extracts from gooseberry (Emblica officinalis), common basil (Ocimum basilicum), and spearmint (Mentha viridis) were relatively less efficient in raising MGMT levels. Increased levels of MGMT mRNA accounted at least, in part, for the increased activity of the DNA repair protein. The herbal treatments also increased glutathione S-transferase-pi (GSTP1) expression, albeit to a lesser extent than MGMT. These data provide the first evidence for the upregulation of human MGMT by plant constituents and raise the possibility of rational dietary approaches for attenuating alkylation-induced carcinogenesis. Further, they reveal the putative anti-oxidant responsiveness of the MGMT gene in human cells.