Carcinogenesis Advance Access published online on August 31, 2006
Carcinogenesis, doi:10.1093/carcin/bgl155
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
1 Anticancer Resistance Research Group, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center, 1400 Wallace Blvd., Amarillo, TX, 79106, USA
* To whom correspondence should be addressed. 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 the 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 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 MGMTexpression, 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-pi (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 putative antioxidant responsiveness of the human MGMT gene.
Received June 13, 2006
Revised July 26, 2006
Accepted August 16, 2006
CANCER PREVENTION
Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines
Suryakant K. Niture 1, Chinavenmani S. Velu 1, Quentin R. Smith 1, G. Jayarama Bhat 1, and Kalkunte S. Srivenugopal 1 *
Kalkunte S. Srivenugopal, E-mail: Kalkunte.srivenugopal{at}ttuhsc.edu
Abstract 
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  D. BOCANGEL, S. SENGUPTA, S. MITRA, and K. K. BHAKAT p53-Mediated Down-regulation of the Human DNA Repair Gene O6-Methylguanine-DNA Methyltransferase (MGMT) via Interaction with Sp1 Transcription Factor Anticancer Res, October 1, 2009; 29(10): 3741 - 3750. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. D. Stoner, L.-S. Wang, and B. C. Casto Laboratory and clinical studies of cancer chemoprevention by antioxidants in berries Carcinogenesis, September 1, 2008; 29(9): 1665 - 1674. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Gatz and L. Wiesmuller Take a break--resveratrol in action on DNA Carcinogenesis, February 1, 2008; 29(2): 321 - 332. [Abstract] [Full Text] [PDF]
|
|