O6-methylguanine-DNA
methyltransferase (MGMT) is
a DNA repair
protein which protects the cellular genome and critical oncogenic genes from the mutagenic action of endogenous and exogenous
alkylating agents. An expedited elimination of O6-alkylguanines by increasing MGMT activity levels is likely to be a successful
chemoprevention strategy. Here, we report for the first time that
cysteine/
glutathione enhancing drugs and certain plant
antioxidants possess the ability to increase human MGMT expression beyond its steady-state levels that may afford protection. The non-toxic
cysteine prodrugs,
2-oxothiazolidine-4-carboxylic acid (OTC) and
N-acetyl-L-cysteine (NAC), metabolized, respectively by
5-oxoprolinase and acylases, increased the MGMT
protein and its repair activity levels in a dose- and time-dependent manner in several
cancer cell lines and peripheral blood lymphocytes with a maximum of 3-fold increase by 72 h. The natural
antioxidants, namely,
curcumin,
silymarin,
sulforaphane and
resveratrol were also effective in raising the MGMT levels to different extents. Among the synthetic agents,
oltipraz and N-(4-hydroxyphenyl)
retinamide (4-HPR) also increased MGMT expression, albeit to a lesser extent. Augmented
mRNA levels accounted at least, in part, for the increased activity of MGMT in this setting. However, evidence from
cysteine/
methionine deprivation,
acivicin treatment, and
protein synthesis measurements in OTC-treated cells suggested that an increased
cysteine flux also contributed significantly to enhanced MGMT expression. Many of these treatments increased the
glutathione S-transferase-P1 (GSTP1) levels as well. These findings raise the possibility of MGMT-targeted
chemoprevention strategies through dietary supplementation of OTC and herbal
antioxidants. Further, the studies reveal the
antioxidant responsiveness of the human MGMT gene.