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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.

Publication ,  Journal Article
Paranjpe, A; Zhang, R; Ali-Osman, F; Bobustuc, GC; Srivenugopal, KS
Published in: Carcinogenesis
March 2014

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. We investigated the effects of DSF on human O(6)-methylguanine-DNA methyltransferase (MGMT), a DNA repair protein and chemotherapy target that removes the mutagenic O(6)-akyl groups from guanines, and thus confers resistance to alkylating agents in brain tumors. We used DSF, copper-chelated DSF or CuCl2-DSF combination and found that all treatments inhibited the MGMT activity in two brain tumor cell lines in a rapid and dose-dependent manner. The drug treatments resulted in the loss of MGMT protein from tumor cells through the ubiquitin-proteasome pathway. Evidence showed that Cys145, a reactive cysteine, critical for DNA repair was the sole site of DSF modification in the MGMT protein. DSF was a weaker inhibitor of MGMT, compared with the established O(6)-benzylguanine; nevertheless, the 24-36h suppression of MGMT activity in cell cultures vastly increased the alkylation-induced DNA interstrand cross-linking, G2/M cell cycle blockade, cytotoxicity and the levels of apoptotic markers. Normal mice treated with DSF showed significantly attenuated levels of MGMT activity and protein in the liver and brain tissues. In nude mice bearing T98 glioblastoma xenografts, there was a preferential inhibition of tumor MGMT. Our studies demonstrate a strong and direct inhibition of MGMT by DSF and support the repurposing of this brain penetrating drug for glioma therapy. The findings also imply an increased risk for alkylation damage in alcoholic patients taking DSF.

Duke Scholars

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Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

March 2014

Volume

35

Issue

3

Start / End Page

692 / 702

Location

England

Related Subject Headings

  • Oncology & Carcinogenesis
  • O(6)-Methylguanine-DNA Methyltransferase
  • Mice
  • Humans
  • Enzyme Inhibitors
  • Disulfiram
  • DNA Damage
  • Cell Line, Tumor
  • Brain Neoplasms
  • Brain
 

Citation

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Paranjpe, A., Zhang, R., Ali-Osman, F., Bobustuc, G. C., & Srivenugopal, K. S. (2014). 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, 35(3), 692–702. https://doi.org/10.1093/carcin/bgt366
Paranjpe, Ameya, 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 35, no. 3 (March 2014): 692–702. https://doi.org/10.1093/carcin/bgt366.
Journal cover image

Published In

Carcinogenesis

DOI

EISSN

1460-2180

Publication Date

March 2014

Volume

35

Issue

3

Start / End Page

692 / 702

Location

England

Related Subject Headings

  • Oncology & Carcinogenesis
  • O(6)-Methylguanine-DNA Methyltransferase
  • Mice
  • Humans
  • Enzyme Inhibitors
  • Disulfiram
  • DNA Damage
  • Cell Line, Tumor
  • Brain Neoplasms
  • Brain