The blood and brain barrier (BBB) and chemoresistance are the major obstacles for the success of glioblastoma multiforme (GBM) chemotherapy. It has been shown that high nuclear factor kappa B (NFκB) activity is highly related to chemoresistance. Gemcitabine (dFdC) can easily cross the BBB and gets into GBM tissues. Due to the chemoresistance of GBM cells to dFdC induced cytotoxicity, this drug is currently only used as a radiosensitiser for GBM treatment. Disulfiram (DS) is an anti-alcoholism medicine. Our previous study demonstrates that DS strongly inhibits NFκB activity and sensitises cancer cell lines to several anticancer drugs including dFdC. DS can freely pass through BBB. Therefore, we tested the chemosensitising effect of DS on dFdC in three GBM cell lines (U251MG, U87MG and U373MG). DS was cytotoxic to GBM cell lines. Copper (Cu) was essential for DS induced cytotoxicity in GBM cell lines. Cu or DS alone was not cytotoxic to GBM cell lines in vitro. Whereas high cytotoxicity (IC50 = 150 - 250 nM) was demonstrated when DS was dosed in combination with physiological concentration of Cu (1 µM). We also tested the chemosensitising effect of DS/Cu complex on dFdC in GBM cell lines. The GBM cell lines were highly resistant to dFdC induced cell death. DS significantly sensitised the cytotoxicity of dFdC in GBM cell lines (∼ 6 - 23-fold; Table 1). CI-isobologram analysis indicated that the combination effect between DS/Cu and dFdC was highly synergistic (Table 1). Flow cytometric data demonstrated that DS/Cu enhanced dFdC induced apoptosis. The molecular chemosensitising mechanisms of DS/Cu to dFdC in GBM cells are still not full elucidated. Our preliminary data indicated that DS/Cu simultaneously inhibited NFκB pathway and triggered reactive oxygen species (ROS)-JNK pathway.

Cytotoxicity of dFdC alone or dFdC plus DS/Cu in GBM cell lines

 U251MGU87MGU373MG
dFdC alone 100.4 (22.3) >400 78.6 (5.6) 
dFdC + DS/Cu (1:10 ratio) 17.5 (5.1) 17.1 (3.0) 6.8 (1.8) 
CI 0.39 0.47 0.82 
 U251MGU87MGU373MG
dFdC alone 100.4 (22.3) >400 78.6 (5.6) 
dFdC + DS/Cu (1:10 ratio) 17.5 (5.1) 17.1 (3.0) 6.8 (1.8) 
CI 0.39 0.47 0.82 

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5380.