Myricetin-induced oxidative stress suppresses murine T lymphocyte activation.

A number of polyphenolic compounds present in fruits and vegetables have the capacity to modulate immune responses; however, the impact of the common plant-derived flavonoid myricetin on T lymphocyte function has not been investigated. We show that myricetin inhibited mouse T lymphocyte activation by bead-immobilized anti-CD3 and anti-CD28 monoclonal antibodies, as indicated by a dose-dependent reduction in cell proliferation and decreased synthesis of interferon-γ, interleukin (IL)-2, IL-4, and IL-17 associated with different T helper cell subsets. This effect was attributed to myricetin-induced reactive oxygen species (ROS) since myricetin caused hydrogen peroxide (H2 O2 ) to accumulate in cell-free culture medium and H2 O2 inhibited T cell proliferation and cytokine synthesis. In addition, the antioxidant N-acetyl cysteine restored the ability of myricetin-treated T lymphocytes to proliferate in response to a mitogenic stimulus. The presence of dendritic cells or bone marrow-derived macrophages negated the inhibitory effect of myricetin on T cell activation, and H2 O2 in T cell cultures that were treated with exogenous H2 O2 was reduced when antigen-presenting cells were also present. These findings suggest that antioxidant molecules produced by dendritic cells and macrophages protected T cells from myricetin-induced oxidative stress, and underscore the importance of considering immune cell interactions when evaluating the immunomodulatory activity of ROS-generating phytochemicals.

Myricetin-induced apoptosis of triple-negative breast cancer cells is mediated by the iron-dependent generation of reactive oxygen species from hydrogen peroxide.

Myricetin is a dietary phytochemical with anticancer activity; however, the effect of myricetin on breast cancer cells remains unclear. Here, we show that myricetin inhibited the growth of triple-negative breast cancer (TNBC) cells but was less inhibitory for normal cells. The effect of myricetin was comparable to epigallocatechin gallate and doxorubicin, and greater than resveratrol and cisplatin. Myricetin-treated TNBC cells showed evidence of early and late apoptosis/necrosis, which was associated with intracellular reactive oxygen species (ROS) accumulation, extracellular regulated kinase 1/2 and p38 mitogen-activated protein kinase activation, mitochondrial membrane destabilization and cytochrome c release, and double-strand DNA breaks. The antioxidant N-acetyl-cysteine protected myricetin-treated TNBC cells from cytotoxicity due to DNA damage. Myricetin also induced hydrogen peroxide (H2O2) production in cell-free culture medium, as well as in the presence of TNBC cells and normal cells. In addition, deferiprone-mediated inhibition of intracellular ROS generation via the iron-dependent Fenton reaction and inhibition of extracellular ROS accumulation with superoxide dismutase plus catalase prevented myricetin-induced cytotoxicity in TNBC cell cultures. We conclude that the cytotoxic effect of myricetin on TNBC cells was due to oxidative stress initiated by extracellular H2O2 formed by autoxidation of myricetin, leading to intracellular ROS production via the Fenton reaction.

Piperine inhibits the growth and motility of triple-negative breast cancer cells.

Piperine, an alkaloid from black pepper, is reported to have anticancer activities. In this study, we investigated the effect of piperine on the growth and motility of triple-negative breast cancer (TNBC) cells. Piperine inhibited the in vitro growth of TNBC cells, as well as hormone-dependent breast cancer cells, without affecting normal mammary epithelial cell growth. Exposure to piperine decreased the percentage of TNBC cells in the G2 phase of the cell cycle. In addition, G1- and G2-associated protein expression was decreased and p21(Waf1/Cip1) expression was increased in piperine-treated TNBC cells. Piperine also inhibited survival-promoting Akt activation in TNBC cells and caused caspase-dependent apoptosis via the mitochondrial pathway. Interestingly, combined treatment with piperine and γ radiation was more cytotoxic for TNBC cells than γ radiation alone. The in vitro migration of piperine-treated TNBC cells was impaired and expression of matrix metalloproteinase-2 and -9 mRNA was decreased, suggesting an antimetastatic effect by piperine. Finally, intratumoral administration of piperine inhibited the growth of TNBC xenografts in immune-deficient mice. Taken together, these findings suggest that piperine may be useful in the treatment of TNBC.