Diallyl disulfide inhibits TNFα induced CCL2 release through MAPK/ERK and NF-Kappa-B signaling

Abstract

TNFα receptors are constitutively overexpressed in tumor cells, correlating to sustain elevated NFκB and monocyte chemotactic protein-1 (MCP-1/CCL2) expression. The elevation of CCL2 evokes aggressive forms of malignant tumors marked by tumor associated macrophage (TAM) recruitment, cell proliferation, invasion and angiogenesis. Previously, we have shown that the organo-sulfur compound diallyl disulfide (DADS) found in garlic (Allium sativum) attenuates TNFα induced CCL2 production in MDA-MB-231 cells. In the current study, we explored the signaling pathways responsible for DADS suppressive effect on TNFα mediated CCL2 release using PCR Arrays, RT-PCR and western blots. The data in this study show that TNFα initiates a rise in NFκB mRNA, which is not reversed by DADS. However, TNFα induced heightened expression of IKKε and phosphorylated ERK. The expression of these proteins corresponds to increased CCL2 release that can be attenuated by DADS. CCL2 induction by TNFα was also lessened by inhibitors of p38 (SB202190) and MEK (U0126) but not JNK (SP 600125), all of which were suppressed by DADS. In conclusion, the obtained results indicate that DADS down regulates TNFα invoked CCL2 production primarily through reduction of IKKε and phosphorylated-ERK, thereby impairing MAPK/ERK, and NFκB pathway signaling. Future research will be required to evaluate the effects of DADS on the function and expression of TNFα surface receptors.

The Progress of Diallyl Disulfide in Anti-Cancer

“…Tumor angiogenesis results in abnormally formed, tortuous, and poorly organized vessels that exhibit altered permeability [108,109]. Previous researches have confirmed that the aberrant activated TNF-α receptor signaling is associated with coordination of tumor angiogenesis and metastasis [110]. DADS can inhibit the CCL2 (CC chemokine-2) releasing induced by TNF-α to play an antiangiogenesis role in MDA-MB-231 cells.…”

Forkhead Box Q1 Is a Novel Target of Breast Cancer Stem Cell Inhibition by Diallyl Trisulfide

“…Cellular models have been utilized to delineate the mechanisms by which garlic constituents may inhibit breast cancer growth (15)(16)(17)(18)(19)(20). For example, DATS treatment inhibited DNA strand breaks induced by an environmental carcinogen (benzo-[a]pyrene) in a non-tumorigenic normal human mammary epi-thelial cell line (MCF-10A) (16).…”

Assessment of transcriptional activity genes associated with the IL‐17 signaling pathway in skin fibroblasts under the influence of adalimumab

“…The analysis carried out by Bauer et al () indicated that in the TNF‐α MDA‐MB‐231 breast cancer cell line, the NFκB transcriptional activity and the components of the MAPK pathway of kinases and CCL2 increase. In addition, these researchers found that the influence of TNF‐α diallyl disulfide is silenced, which involves the NFκB and MAPK pathways of the kinases.…”

“…Bauer et al () suggest its potential use to control the expression of TNF‐α and its surface receptors. This analysis also seems to confirm the assumed hypothesis of the complex and mutually interacting influence of the individual components of signaling cascades on themselves.…”

“…The analysis carried out by Bauer et al (2015) indicated that in the TNF-α MDA-MB-231 breast cancer cell line, the NFκB transcriptional activity and the components of the MAPK pathway of kinases and CCL2…”