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6-Gingerol is a bioactive compound isolated from Zingiber officinale. 6-Gingerol has been shown to have anticancer effects in numerous types of cancer cell. The mechanisms underlying the anticancer effect of 6-Gingerol in prostate cancer requires investigation. In the present study, the effect on cell viability of 6-Gingerol on LNCaP, PC3 and DU145 prostate cancer cells were determined using the MTT and colony formation assays. 6-Gingerol significantly inhibited cell migration, adhesion and invasion in LPS-stimulated and LPS-unstimulated prostate cancer cells. Furthermore, these changes were accompanied by alterations in the protein expression levels of epithelial-mesenchymal transition biomarkers, including E-cadherin, N-cadherin, Vimentin and zonula occludens-1. 6-Gingerol also induced autophagy by significantly increasing LC3B-Ⅱ and Beclin-1 protein expression levels in prostate cancer cells. Combining 6-Gingerol with LY294002, an autophagy inhibitor, significantly increased cell survival in DU145 cells. Furthermore, 6-Gingerol significantly decreased the protein expression levels of glutathione (GSH) peroxidase 4 and nuclear factor erythroid 2-related factor 2 in prostate cancer cells. Reactive oxygen species (ROS) levels were significantly increased but GSH levels were decreased following 6-Gingerol treatment in prostate cancer cells. Co-treatment with the ferroptosis inhibitor, ferrostatin-1, significantly increased cell viability and significantly decreased ROS levels in 6-Gingerol-treated cells. These results suggested that 6-Gingerol may have inhibited prostate cell cancer viability via the regulation of autophagy and ferroptosis. In addition, 6-Gingerol inhibited cell migration, adhesion and invasion via the regulation of EMT-related protein expression levels in LPS-stimulated and LPS-unstimulated prostate cancer cells. In conclusion, 6-Gingerol may induce protective autophagy, autophagic cell death and ferroptosis-mediated cell death in prostate cancer cells. These findings may provide a strategy for the treatment and prevention of prostate cancer.

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Background: Diazepam is a benzodiazepine drug used to treat anxiety, insomnia, and muscle spasms. Imperatorin is a phytochemical isolated from medicinal plants and is widely used in herbal medicine. The aim of this study was to investigate the interactions between imperatorin and diazepam in vitro and in vivo and to provide evidence-based guidance for the safe clinical use of the drug. Methods: In vitro inhibition of imperatorin was assessed by incubating rat liver microsomes with diazepam to determine IC 50 values and the type of inhibition. For in vivo assessment, six rats were pretreated with 50 mg/kg imperatorin for two weeks, six were administered saline, and a single dose of 10 mg/kg diazepam was administered orally to both groups 30 min after the administration of imperatorin. Results: Imperatorin inhibited the in vitro metabolism of diazepam via the competitive mechanism of CYP450. The IC 50 values of imperatorin to nordazepam and temazepam were 1.54 mM and 1.80 mM, respectively. The inhibitory constant values for temazepam and nordazepam were 1.24 mM and 1.29 mM, respectively. Long-term administration of imperatorin significantly increased the AUC (0-12h) , AUC (0-∞) , and Cmax of diazepam, while Vz/F and CLz/F were decreased significantly (P < 0.05). In turn, the AUC (0-12h) , AUC (0-∞) , and Cmax of nordazepam and temazepam decreased significantly, and Vz/F and CLz/F increased significantly (P < 0.05). Conclusions: This study demonstrates that imperatorin inhibits the metabolism of diazepam both in vitro and in vivo. These results indicated that more attention should be paid when taking diazepam together with food or herbs containing IMP, although further investigation is still needed.