Diallyl trisulfides, a natural histone deacetylase inhibitor, attenuate HIF-1 synthesis, and decreases breast cancer metastasis

Intratumoral hypoxia promotes the distant metastasis of cancer subclones. The clinical expression level of hypoxia-inducible factor-1 (HIF-1) reflects the prognosis of a variety of cancers, especially breast cancer. Histone deacetylase (HDAC) inhibitors can target HIF-1 protein due to von Hippel-Lindau (VHL) protein-dependent degradation. Dietary organosulfur compounds, such as those in garlic, have been reported as HDAC inhibitors. The effects of diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS) on the ratio of firefly/Renilla luciferase activity in hypoxic MDA-MB-231 cells were determined. The mRNA expressions of HIF-1 target genes ANGPTL4, LOXL4, and LOX in hypoxic MDA-MB-231 cells were significantly down-regulated by DATS. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish, xenograft, and orthotopic tumors. Endothelial cell-cancer cell adhesion, wound healing, transwell, and tube formation assays showed that DATS dose-dependently inhibited the migration and angiogenesis of MDA-MB-231 cells in vitro. The expressions of L1CAM, VEGF-A, and EMT-related proteins (Slug, Snail, MMP-2) were inhibited by DATS. DATS dose-dependently inhibited HIF-1 transcriptional activity and hypoxia-induced hematogenous metastasis of MDA-MB-231 cells. It reduced the protein expression of HIF-1, which did not involve inhibition of HIF-1 mRNA expression or ubiquitin proteasome degradation. Efficient inhibition of HIF-1 expression was required for DATS to resist breast cancer.