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- Title
Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity.
- Authors
Tomooka, Fumimasa; Kaji, Kosuke; Nishimura, Norihisa; Kubo, Takahiro; Iwai, Satoshi; Shibamoto, Akihiko; Suzuki, Junya; Kitagawa, Koh; Namisaki, Tadashi; Akahane, Takemi; Mitoro, Akira; Yoshiji, Hitoshi
- Abstract
Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial–mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.
- Subjects
ANTINEOPLASTIC agents; CELL cycle; CHOLANGIOCARCINOMA; SULFORAPHANE; HISTONE deacetylase
- Publication
Cells (2073-4409), 2023, Vol 12, Issue 5, p687
- ISSN
2073-4409
- Publication type
Article
- DOI
10.3390/cells12050687