The garlic compound ajoene targets protein folding in the endoplasmic reticulum of cancer cells

Abstract

Ajoene is a natural allylsulfur compound found in crushed garlic that arrests growth and induces apoptosis in cancer cells. To gain mechanistic insights into the cytotoxicity of ajoene in cancer cells, two fluorescently labelled ajoene analogs with dansyl- (DP) and fluorescein- (FOX) tags were synthesized. The tagged ajoenes were found to retain their activity at inhibiting proliferation and inducing apoptosis in MDA-MB-231 human breast-cancer and WHCO1 human esophageal-cancer cells. Both tagged ajoenes localized to the endoplasmic reticulum (ER) in MDA-MB-231 cells as observed by live cell confocal laser scanning microscopy (CLSM) and confirmed by generating an MDA-MB-231 cell line expressing yellow fluorescent protein (YFP) in the ER. DP appears to S-thiolate multiple protein targets in MDA-MB-231 cells as observed by immunoblotting under non-reducing conditions only; and a competition assay demonstrated that DP and Z-ajoene in fact share the same target. Ajoene S-thiolation interfered with protein folding and led to an accumulation of misfolded protein aggregates and activated the unfolded protein response (UPR). Consistent with this mechanism, increased levels of GRP78 and total ubiquitinated proteins were observed; and an ER-folded protein, type-1 collagen, was tracked to the proteasome following ajoene treatment. The intracellular protein aggregates were observed by CLSM and transmission electron microscopy (TEM). This is the first time that ajoene has been shown to target protein folding in the ER of cancer cells. © 2015 Wiley Periodicals, Inc.

Stability and extraction of bioactive sulfur compounds from Allium genus processed by traditional and innovative technologies

“…Furthermore, recent studies have associated garlic consumption with preventive effects on human cancer (Chiavarini et al, 2016;de Giorgio and Stebbing, 2016;Kaschula et al, 2016;Myneni et al, 2016;Saud et al, 2016;Smith et al, 2016). The hypothesis underlying these studies may partially be explained by the anti-mutagenic and immune-modulatory effects of garlic derived allylsulfur compounds and their ability to exert a direct anti-proliferative effect on growing tumour cells by inducing apoptosis Powolny and Singh, 2008;Schafer and Kaschula, 2014).…”

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

“…Garlic‐derived organosulfur compounds, including diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS), are HDAC inhibitors with anticarcinogenic properties . In particular, DADS and DATS can modulate numerous biological mechanisms that may influence carcinogenesis in non‐tumor colon, glioblastoma, stomach cancer, and others . We have reported that DADS was a promising cancer chemopreventive agent for a skin carcinogenic model through p21‐dependent Nrf2 stabilization .…”

“…[19][20][21] In particular, DADS and DATS can modulate numerous biological mechanisms that may influence carcinogenesis in non-tumor colon, glioblastoma, stomach cancer, and others. [22][23][24][25] We have reported that DADS was a promising cancer chemopreventive agent for a skin carcinogenic model through p21dependent Nrf2 stabilization. 26 DATS inhibited MMP2/9 activity and the metastasis of breast cancer cells in vitro, as a potential anticancer agent.…”

The 15th Frank Warren Organic Chemistry Conference

“…Anke Wilhelm (University of the Free State) divulged her recent results in HPLC‐based activity profiling in a zebrafish locomotive assay for the identification of GABA A receptor modulators (Figure ) . Dr. Catherine Kaschula gave us an update on her ongoing studies into the cancer preventative properties of ajoene and related garlic analogues as well as the biological activity of their synthetic analogies and the potential biological targets of these compounds …”