Sulforaphane Potentiates Gemcitabine-Mediated Anti-Cancer Effects against Intrahepatic Cholangiocarcinoma by Inhibiting HDAC Activity.
Fumimasa TomookaKosuke KajiNorihisa NishimuraTakahiro KuboSatoshi IwaiAkihiko ShibamotoJunya SuzukiKoh KitagawaTadashi NamisakiTakemi AkahaneAkira MitoroHitoshi YoshijiPublished in: Cells (2023)
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.
Keyphrases
- cell cycle arrest
- cell death
- histone deacetylase
- pi k akt
- cell cycle
- induced apoptosis
- epithelial mesenchymal transition
- endothelial cells
- signaling pathway
- poor prognosis
- combination therapy
- endoplasmic reticulum stress
- oxidative stress
- cell proliferation
- vascular endothelial growth factor
- binding protein
- cardiovascular disease
- transforming growth factor
- squamous cell carcinoma
- adipose tissue
- high throughput
- metabolic syndrome
- risk factors
- locally advanced
- risk assessment
- induced pluripotent stem cells
- papillary thyroid
- diabetic rats
- nitric oxide
- radiation therapy
- drinking water
- health risk
- skeletal muscle
- lymph node metastasis
- climate change