Description:
MGMT is a DNA repair protein that interferes with the cytotoxic action of alkylating chemotherapy agents. Because of the prevalence of this protein in tumors, especially brain tumors, there is a great need for the discovery of an inhibitor that will not harm bone marrow stem cells. This invention has solved this problem through the discovery of a novel use for an existing FDA approved drug used for the treatment of alcoholism, disulfiram.
Reference Number: D-1000
Market Applications:
Features, Benefits, and Advantages:
The alcohol aversion drug disulfiram (DSF) reacts and conjugates with the protein-bound nucleophilic cysteines and is known to elicit anticancer effects alone or improve the efficacy of many cancer drugs. This invention investigated the effects of disulfiram on human MGMT, a DNA repair protein and chemotherapy target that removes the mutagenic O6-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors. Treatment with DSF inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner. DSF was a weaker inhibitor of MGMT, compared to the established O6-benzylguanine, nevertheless, the 24-36 h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand crosslinking, G2/M cell cycle blockade, cytotoxicity, and the levels of apoptotic markers.
- Increased efficacy of cancer treatment
- Decreased side-effects, as compared to existing MGMT inhibitors
Intellectual Property:
A U.S. national stage patent application 15/116,757 was filed on 08/04/2016.
Development Stage:
This technology has been produced and tested.
Researchers:
Kalkunte Srivenugopal, Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, Texas
Publications:
Ameya Paranjpe, Ruiwen Zhang, Francis Ali-Osman, George C. Bobustuc, and Kalkunte S. Srivenugopal
Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage, Carcinogenesis 2014 35: 692-702
Keywords:
pediatric brain cancer, disulfiram, MGMT inhibitors, guinines, chemotherapy