B178
Enhance cytoxoxicity of gemcitabine to resistant cancer cell lines by disulfiram, an antialcoholism drug
Xiaoxia Guo1, Shuchita Pandey1, Sumi Mathew1, Sarah Brown1, Angel Armessila1, John Darling1, James Cassidy2, Weiguang Wang1
1University of Wolverhampton, Wolverhampton, UK, 2University of Glasgow, Glasgow, UK
Gemcitabine (2´, 2´-Difluorodeoxycytidine, dFdC) and fluorouracil (5-FU) belong to anti-metabolic anticancer agents used in the treatment of a wide range of solid cancers. Chemoresistance is the major obstacle for the success of dFdC- and 5-FU-based chemotherapy.
The molecular mechanisms involved in dFdC and the cross-resistance between dFdC and 5-FU are still not fully elucidated. In this study, the chemoresistant status in 5-FU resistant (H630R10 and MCF7FU2.5) and dFdC resistant (H630GEM and HCT116GEM) cell lines were investigated. MTT showed that dFdC resistant cell lines were highly resistant to dFdC (>2,000-fold). High (>2,000-fold) and mild (3.0-fold) cross-resistance to dFdC was detected in 5-FU resistant H630R10 and MCF7FU2.5 cell lines respectively. The dFdC resistant cell lines only showed mild resistance to 5-FU (1.5 – 3.0-fold). The dFdC resistant cell lines demonstrated dCK protein down-regulation and thymidylate synthase protein over-expression which may be responsible for their dFdC resistance and the cross-resistance to 5-FU respectively. All resistant cell lines apart from HCT116GEM manifested high NF-κB DNA binding and transcriptional activity. The NF-κB p50 and p65 subunits transfected MCF7 cell lines manifested moderate resistance to dFdC (~ 3.2 – 4.0-fold). We have previously showed that an antialcoholism drug, disulfiram, effectively sensitizes colon cancer cell lines to 5-FU. In this study, the sensitizing effect of disulfiram on the cytotoxicity of dFdC to the chemoresistant cell lines was examined. Disulfiram significantly sensitized cancer cell lines to dFdC and effectively reversed dFdC resistance.
The data from this study indicated that targeting NF-κB pathway may improve therapeutic effect of dFdC.
