Carcinogenesis Advance Access originally published online on August 31, 2006
Carcinogenesis 2007 28(2):378-389; doi:10.1093/carcin/bgl155
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Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines
Anticancer Resistance Research Group, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center 1400 Wallace Boulevard, Amarillo, TX 79106, USA
*To whom correspondence should be addressed. Tel: +806 356 4660, Ext. 221; Fax: +806 356 4663; Email: Kalkunte.srivenugopal{at}ttuhsc.edu
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.
Abbreviations: MGMT, O6-methylguanine-DNA methyltransferase; DTT, dithiothreitol; BCNU, 1,3-bis(2-chloroethyl)-1-nitrosourea; BG, O6-benzylguanine; HPBL, human peripheral blood lymphocyte; GSTP1, Glutathione S-tranferase P1; OTC, L-2-oxothiazolidine-4-carboxylic acid; NAC, N-acetyl-L-cysteine, 4-HPR, N-(4-hydroxyphenyl) retinamide, 
-GGT, -glutamyltranspeptidase
Received June 13, 2006; revised July 26, 2006; accepted August 16, 2006.
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