Increased expression of the MGMT repair protein mediated by cysteine prodrugs and chemopreventative natural products in human lymphocytes and tumor cell lines.
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.
Niture
Suryakant K
SK
Anticancer Resistance Research Group, Department of Pharmaceutical Sciences, Texas Tech University Health Sciences Center 1400 Wallace Boulevard, Amarillo, TX 79106, USA.
Velu
Chinavenmani S
CS
Smith
Quentin R
QR
Bhat
G Jayarama
GJ
Srivenugopal
Kalkunte S
KS
D000111:Acetylcysteine / Q000494:pharmacology; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D001483:Base Sequence; D001688:Biological Products / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology; D003545:Cysteine / Q000737:chemistry*; D015254:DNA Modification Methylases; D017931:DNA Primers; D045643:DNA Repair Enzymes; D004305:Dose-Response Relationship, Drug; D017313:Fenretinide / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism; D051549:Glutathione S-Transferase pi / Q000378:metabolism; D006801:Humans; D008214:Lymphocytes / Q000378:metabolism*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology*; D011719:Pyrazines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D012838:Silymarin / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins
D016588:Anticarcinogenic Agents; D000975:Antioxidants; D001688:Biological Products; D017931:DNA Primers; D011355:Prodrugs; D011719:Pyrazines; D012333:RNA, Messenger; D012838:Silymarin; D013871:Thiones; D013876:Thiophenes; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins; D017313:Fenretinide; C026209:oltipraz; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D051549:Glutathione S-Transferase pi; D045643:DNA Repair Enzymes; D005978:Glutathione; D003474:Curcumin; D003545:Cysteine; D000111:Acetylcysteine