Regulations of expressions of rat/human sulfotransferases (SULTs) by anti-cancer drug, nolatrexed and micronutrients.

Abstract

Cancer is a disease related to cellular proliferative-state. Drastically increase in cell-cycle regulations augments cellular folate-pool and folate-metabolism. So, this pathway is targeted therapeutically. A number of drugs are involved in this metabolism i.e. folic-acid/folinic-acid/nolatrexed(NT)/ methotrexate(MTX) for the research and treatment of cancer. Our previous study showed that MTX significantly modulated rat/human SULTs. Present study was an attempt to study the effect of NT (widely used in different cancers) and these micronutrients on the expressions of rat/human SULTs. Male Sprague-Dawley rats were treated with NT (01,10 or 100 mg/Kg) or both sexes were treated to folic acid (100,200 or 400 mg/kg) for 2-weeks and their AST-IV (2-napthol sulfation) and STa (DHEA-sulfation) activities, protein-expression (Western-Blot) and mRNA-expression (RT-PCR) were tested. In cultured HepG2 cells NT (1nM-1.2mM) or folonic-acid (10nM-10M) were applied for 10 days. Folic acid (0-10M) was treated to human hepatocarcinoma (HepG2) cells. PPST (phenol-catalyzing), MPST (dopamine) DHEAST (dehydroepiandrosterone,DHEA) and EST (estradiol-sulfating) protein-expressions (Western-blot) were tested in all HepG2 study. Present results suggest NT significantly increased SULTs expressions in rat (protein/mRNA/activity) and HepG2 cells. Folic acid increased SULTs activity/protein in sex-dependant manner (ASTIV in female/ STa in male). Both folic and folinic acid increased several hSULTs isoforms with varied level of significance (least or no increase at highest-dose) in HepG2 cells pointing its dose-dependent multi-phasic responses. The clinical importance of this study may be furthered in the verification of sulfation-metabolism of several exogenous/endogenous molecules, drug-drug interaction and their influences on the patho-physiological processes. Further studies are necessary in this regard.