Bo Su

Diallyl trisulfide (DATS), an organosulfur compound from the common food garlic, has been attracting attention by exhibiting low toxicity, tumor susceptibility, and, especially, multiple antitumor activities, despite its simple molecular structure. The mounting data suggest that the effects of DATS are related to its induction of oxidative stress cell death in various forms via reactive oxygen species (ROS), such as apoptosis, ferroptosis, autophagy, and pyroptosis. Disruption of redox equilibrium by DATS involves not only the induction of ROS generation but also the inhibition of ROS scavenging through modulation of antioxidant systems, which in turn affects the redox-dependent key molecules in the signaling pathways, consequently curbing the malignant behavior of cancers. Retracing the progress of DATS antitumor research in the past decade, we conduct an in-depth analysis of the multitarget mechanisms of DATS intervening in redox homeostasis. This review provides clues for future studies to further reveal its potential antitumor effects.

Objectives: Gastric cancer (GC) is often associated with high invasiveness, epithelial-mesenchymal transition (EMT), and resistance to 5-fluorouracil (5-FU), highlighting the need for novel therapeutic targets. This study explored whether diallyl disulfide (DADS) upregulates retinoic acid-related orphan receptor alpha (ROR) to weaken the protein kinase C alpha (PKC)/RORα-mediated RORα/β-catenin pathway, thereby inhibiting GC cell invasion, epithelial-mesenchymal transition (EMT), and enhancing 5-FU sensitivity. Methods: Human GC cell lines MGC-803 and SGC7901 were treated with DADS, RORα agonist SR1078/antagonist T0901317, and PKCα agonist TPA/antagonist GO6976. Cell proliferation (MTT), migration (scratch assay), invasion (Transwell), protein expression (Western blot), protein interactions (coimmunoprecipitation), and localization (immunofluorescence) were detected. Apoptosis and 5-FU sensitivity-related proteins were examined. Experiments were triplicated; statistics used t-test/ANOVA (p < 0.05). Results: DADS/SR1078 inhibited GC cell proliferation/migration/invasion, upregulated RORα/E-cadherin, downregulated nuclear β-catenin/TGF-β1/Rac1/Vimentin, and weakened EMT (reversed by T0901317). DADS/TPA upregulated RORα/p-RORα/PKCα/p-PKCα, promoted PKCα-RORα binding, and downregulated RORα/β-catenin target genes (counteracted by GO6976). DADS upregulated caspase-3 and downregulated Bcl-2/P-gp/XIAP via RORα, promoting apoptosis and 5-FU sensitivity. Conclusion: DADS inhibits GC progression and enhances 5-FU sensitivity by PKCα/RORα-mediated downregulation of RORα/β-catenin signaling, paralleling SR1078/TPA effects. It may act as a novel RORα agonist for GC therapy.

Diallyl disulfide (DADS), an organic component of allicin abstracted from garlic, possesses multi‐target antitumor activity. DJ‐1 performs a vital function in promoting AKT aberrant activation via down‐regulating phosphatase and tensin homologue (PTEN) in tumors. It is unknown the involvement of DJ‐1 in epithelial–mesenchymal transition (EMT) of gastric cancer (GC) cells. The purpose of this study is to investigate whether diallyl disulfide (DADS) intervenes in the role of DJ‐1 in GC. Based on the identification that the correlation between high DJ‐1 and low PTEN expression in GC was implicated in clinical progression, we illuminated that down‐regulation of DJ‐1 by DADS aided in an increase in PTEN expression and a decrease in phosphorylated AKT levels, which was in line with the results manifested in the DJ‐1 knockdown and overexpressed cells, concurrently inhibiting proliferation, EMT, migration, and invasion. Furthermore, the antagonistic effects of DADS on DJ‐1 were observed in in vivo experiments. Additionally, DADS mitigated the DJ‐1‐associated drug resistance. The current study revealed that DJ‐1 is one of potential targets for DADS, which hopefully provides a promising strategy for prevention and adjuvant chemotherapy of GC.

Overactivation of Wnt/β-catenin pathway due to dysfunction of retinoid-related orphan receptor α (RORα) is related to cancer development and progression. Diallyl disulfide (DADS), an active component of garlic, has been reported in our previous study for upregulation of RORα expression in gastric cancer (GC) cells. It remains to be elucidated the role and mechanism of RORα in DADS against GC. This study revealed that DADS treatment resulted in reduced expression levels of Wnt1, β-catenin, TCF-4, intranuclear β-catenin and p-β-catenin in GC cells, concomitant with the compromised expression of β-catenin target genes (Axin, c-Jun, and c-Myc). RORα overexpression augmented DADS-induced downregulation of Wnt1/β-catenin pathway, G2/M phase arrest, and cell growth inhibition in vitro and in vivo. Contrarily, knockdown of RORα attenuated these effects of DADS. Interestingly, DADS induced an increase in the binding of RORα to β-catenin, which may lead to reduction of β-catenin phosphorylation and nuclear translocation. This interplay modulated by DADS may affect β-catenin target gene expression for that the opposite results were observed in DADS-treated RORα knockdown and overexpression cells. DADS caused a decrease in vimentin, snail and MMP-9, as well as an increase in E-cadherin and TIMP3 expression, which restricted epithelial‑mesenchymal transition (EMT), migration, and invasion. The aforementioned effects of DADS were weakened simultaneously when the suppression of DADS on the Wnt1/β-catenin pathway was resisted by knockdown of RORα. In contrast, overexpression of RORα enhanced the effects of DADS. Therefore, RORα-mediated downregulation of Wnt1/β-catenin pathway could undertake an important role in anticancer activity of DADS against GC cell proliferation, EMT, migration, and invasion.