Background/Aim: Diallyl trisulfide (DATS) has been shown to prevent and inhibit breast carcinogenesis. CCL2/MCP-1 has been shown to play a significant role in breast cancer. This study explored DATS efficacy on triple-negative breast cancer (TNBC) cells. Materials and Methods: DATS efficacy on TNFα induced TNBC cells were examined via trypan blue exclusion test, wound-healing assay, human cytokine arrays, ELISA, and RT-PCR. Results: DATS significantly induced cell death and inhibited cell migration. Expression of CCL2/MCP-1, IL-6, PDGF-BB, NT-3, and GM-CSF in TNF-α-treated cells increased. However, DATS significantly decreased the expression of CCL2/MCP-1 in TNF-α-treated MDA-MB-231 but not in MDA-MB-468 cells. DATS significantly down-regulated mRNA expression of IKBKE and MAPK8 in both cell lines, indicating a possible effect in genes involved in the NF-ĸB and MAPK signaling. Conclusion: DATS may have a role in TNBC therapy and prevention by targeting CCL2.
Background/Aim: Diallyl trisulfide (DATS) has been shown to prevent and inhibit carcinogenesis in cancer cells. We have previously shown DATS's ability to decrease the percentage of viable cells, inhibit cell migration and modulate genes involved in the nuclear factor kappa-light-chainenhancer of activated B cells (NF-ĸB) and mitogen-activated protein kinase (MAPK) signaling. Materials and Methods: This study aimed to compare the efficacy of DATS in tumor necrosis factor alpha (TNF-α) induced MDA-MB-231 and MDA-MB-468 cells and investigate its role in cell-death signaling via cell cycle, flow cytometry, and caspase assay. Results: DATS exhibit a time-dependent accumulation of G 2 /M phase cells in both cell lines, with higher effects in the MDA-MB-468 for all time points. DATS's ability to decrease the percentage of viable cells in both MDA-MB-231 and MDA-MB-468 cells was shown by a significant but slight increase of early and late apoptosis in the presence of DATS comparedto control. Moreover, MDA-MB-468 cells showed more sensitivity to the DATS effect, evidenced by the higher percentage of apoptosis than MDA-MB-231 cells. The caspase studies showed a significant increase in caspase 3 and 8 activity in the presence of DATS, compared to control, in both cell lines. DATS showed no significant increase in caspase 9 activity in both cell lines compared to the control. Conclusion: DATS-induced apoptosis in human breast cancer cells is mediated, at least in part, by cell cycle arrest and caspase activity. These findings provide information for future studies into the role of DATS in TNBC therapy and prevention.
Inflammation and immune response play a key role in triple‐negative breast cancer (TNBC) progression and metastasis. Previous studies have shown that CCL2 plays a significant role in breast cancer cell signaling and can increase cell proliferation and differentiation, immune suppression, epithelial‐to‐mesenchymal transition, and angiogenesis. CCL2 expression is modulated via mitogen‐activated protein kinase (MAPK) and nuclear factor‐kappa beta (NFĶB) signaling pathways. Compounds that can inhibit the release of CCL2 have been shown to prevent cancer‐associated inflammatory and pro‐oncogenic processes. Diallyl Trisulfide (DATS), an organosulfide found in garlic, has been previously reported to be effective in chemoprevention, apoptosis, and cell cycle arrest in DNA damaged normal breast epithelial cells, breast cancer cells, as well as other cancers. The current study explored the effect of DATS on the genetically different TNBC MDA‐MB‐231 and MDA‐468 cells, stimulated by TNF‐α. Cytokine arrays, ELISA, and RT‐PCR using individual primers were used. DATS downregulated CCL2 protein expression in MDA‐MB‐231, but not in MDA‐MB‐468 cells. These results were confirmed with ELISA analysis that showed a reduction in the expression of CCL2 in the TNF‐α stimulated MDA‐MB‐231 cells treated with DATS. The data also showed that DATS treatment reduced by 50% the mRNA expression of CCL2 in MDA‐MB‐231cells after a 24‐h period. To study a possible mechanism for DATS inhibitory effect over CCL2 expression, this compound's effect on the mRNA expression of IKBKE and MAPK8, which belong to the NFĶB and MAPK signaling pathways, respectively, was also investigated. DATS downregulated both genes in the TNF‐α stimulated MDA‐MB‐231 and MDA‐MB‐468 cells. In conclusion, this study showed that DATS could downregulate CCL2 expression in the protein and transcription level in MDA‐MB‐231 cells. A possible mechanism for DATS inhibitory effect may involve the downregulation of IKBKE and MAPK8 mRNA expression. IKBKE gene was reported to be overexpressed in approximately 30% of human breast tumors and promotes cytokine release and pro‐survival signaling through the activation of NFĶB and JAK‐STAT pathways. Our findings demonstrate that DATS may have potential in breast cancer treatment, slowing down cancer progression by the downregulation of CCL2 expression and that genetically different TNBC cells may respond differently to DATS treatment.
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