P4 Diallyl Trisulfides, a garlic-derived organosulfur compound, attenuates vascular metastasis of hypoxic breast cancer cells by targeting the thioredoxin system

Abstract

Metastasis is the leading cause of high mortality in breast cancer patients. As is shown by numerous clinical studies and research data, intra-tumor hypoxia is closely related to the fatality rate of breast cancer patients, which may suggest that HIF-1α expression plays a contributory role in breast cancer metastasis. DATS was screened out from the garlic fat-soluble components on the basis of HIF-1α transcriptional activity. DATS not only demonstrated that it could effectively inhibit HIF-1α transcriptional activity, but that it also affected the mRNA levels of its direct target genes LOX, ANGPTL4 and LOXL-4 to varying degrees. DATS attenuated the metastatic potential of MDA-MB-231 cells in hypoxia-induced embryonic zebrafish assays, xenograft and orthotopic tumor assays. Those results also showed that DATS could dose-dependently inhibit the migration and angiogenesis of MDA-MB-231 cells using EC-cancer cell adhesion, wound-healing, transwell and tube formation in vitro experiments. Inhibition of L1CAM, EMT-related proteins (Slug, Snail, MMP-2) and VEGF-A protein expression was also induced by DATS. DATS modulates HIF-1α not only at the protein level but also via direct inhibition of its activity through its effects on upstream Trx-1 protein level. DATS also inhibits the enzyme activity of Trx reductase in breast cancer cells. In keeping with reduced Trx-1 nuclear translocation from cytoplasm by DATS, the production of the reduced form of Trx-1 was dramatically decreased. Collectively, this present study indicates that targeting the Trx system with DATS may provide a promising strategy for treating metastasis in breast cancer.