Cholangiocarcinomas are devastating
cancers that are resistant to
chemotherapies.
Resveratrol, a food-derived
polyphenol with antitumorigenic properties, can regulate the expression of
cytochrome p450 1b1 (Cyp1b1), which may confer chemoresistance in various
cancers. Our aims were to assess the effects of
resveratrol on the sensitivity of
cholangiocarcinoma cells to chemotherapeutic agents and show an association between Cyp1b1 expression and chemosensitivity.
Cholangiocarcinoma cell lines were treated with
resveratrol before the addition of
5-fluorouracil (5-FU),
gemcitabine, or
mitomycin C. Cell proliferation and apoptosis were assessed by MTS assays and
Annexin staining.
Resveratrol effects on
cholangiocarcinoma tumor sensitivity to
5-FU was assessed in an in vivo xenograft model using Mz-ChA-1 cells. After
resveratrol treatment, Cyp1b1 expression was assessed by real-time PCR and immunoblotting. Stable-transfected cell lines with Cyp1b1 expression knocked down (Mz-Cyp1b1) were used to assess sensitivity to chemotherapeutic agents by MTS assays and
Annexin staining and in a xenograft model using Mz-ChA-1 and Mz-Cyp1b1 cells, respectively. For each chemotherapeutic agent, co-treatment with
resveratrol in vitro decreased cell proliferation and increased apoptosis to a greater extent than with the chemotherapeutic agent alone. In vivo, 5-FU+resveratrol decreased
tumor size and increased TUNEL staining to a greater extent than
5-FU alone. In parallel,
resveratrol decreased Cyp1b1 expression in Mz-ChA-1 cells and in
cholangiocarcinoma tumors. Mz-Cyp1b1 cells were more sensitive to chemotherapeutic agents in vitro than mock-transfected cells, and Mz-Cyp1b1-induced
tumors were more susceptible to
5-FU treatment. We suggest that
resveratrol treatment may be a useful adjunct
therapy to improve chemosensitivity in
cholangiocarcinoma.