Promising Effects of Zerumbone on the Regulation of Tumor-promoting Cytokines Induced by TNF-α-activated Fibroblasts

Inflammation plays an important role in the development of several cancers. Inflammatory cytokines, including tumor necrosis factor-alpha (TNF-alpha), are associated with the induction of inflammation. Chronic inflammation contributes to the progression of cancer through several mechanisms, including increased cytokine production and activation of transcription factors, such as nuclear factor-kappa B (NF-kappa B). Zerumbone (ZER), a component of subtropical ginger (Zingiber zerumbet Smith), seems to have anti-inflammatory, anti-cancer, and antioxidant activities. In this study, we aimed to explore the protective function and mechanisms of ZER against TNF-alpha-induced cancer-promoting cytokines. We found that the viability of stimulated human fibroblast cell lines was reduced after treatment with ZER (IC50=18 mu mol/L), compared to un-stimulated fibroblasts (IC50=40 mu mol/L). Besides, ZER inhibited mRNA expression and protein secretion of transforming growth factor-beta (TGF-beta), interleukin-33 (IL-33), monocyte chemoattractant protein-1 (MCP-1), and stromal cell-derived factor 1 (SDF-1), which were produced by TNF-alpha-induced fibroblasts, as measured by quantitative real time-PCR (qRT-PCR) and ELISA assays. The mRNA expression levels of TGF-beta, IL-33, SDF-1, and MCP-1 showed 8, 5, 2.5, and 4-fold reductions, respectively. Moreover, secretion of TGF-beta, IL-33, SDF-1, and MCP-1 was reduced to 3.65 +/- 0.34 ng/mL, 6.3 +/- 0.26, 1703.6 +/- 295.2, and 5.02 +/- 0.18 pg/mL, respectively, compared to the untreated group. In addition, the conditioned media (CM) of TNF-alpha-stimulated fibroblasts increased the NF-kappa B expression in colorectal cancer cell lines (HCT-116 and Sw48), while in the vicinity of ZER, the expression of NF-kappa B was reversed. Considering the significant effects of ZER, this component can be used as an appropriate alternative herbal treatment for cancer-related chronic inflammation.