Nobiletin inhibits breast cancer via p38 mitogen-activated protein kinase, nuclear transcription factor-κB, and nuclear factor erythroid 2-related factor 2 pathways in MCF-7 cells

Abstract

IntroductionBreast cancer is one of the most commonly diagnosed cancers in women, with a high mortality rate.ObjectiveIn the present study, we evaluated the anticancer effect of nobiletin, a flavone glycoside, on the breast cancer cell line MCF-7.ResultCell viability and proliferation decreased and cell morphology changed from diamond to round after being treated with nobiletin. Nobiletin induced apoptosis of breast cancer MCF-7 cells via regulating the protein expression of Bax, Bcl-2, cleaved caspase-3, and p53. The expression of Bcl-2 decreased, while the expression of Bax and p53 increased in MCF-7 cells treated with nobiletin. Meanwhile, nobiletin inhibited cell migration by downregulating the protein expression of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). Moreover, phosphorylation of p38 was increased, and the translocation of p65 and nuclear factor erythroid 2-related factor 2 (Nrf2) to the nucleus was decreased, which suggested that the anticancer effects of nobiletin might at least partially rely on mediating the p38 mitogen-activated protein kinase, nuclear transcription factor-κB, and Nrf2 pathways in MCF-7 breast cancer cells.Conclusion and recommendationOur data showed that nobiletin was a potential antitumor drug, and it provided some experimental basis for the clinical application of tumor therapy.

Nobiletin Affects Circadian Rhythms and Oncogenic Characteristics in a Cell-Dependent Manner

“…21 It may induce apoptosis and inhibit cell migration via MAPK and/or MAPK/AKT related pathways. 22,23 Similar anti-proliferative effects have been observed in high tumor grade MDA-MB-231 23 and MDA-MB-468 human breast cancer cells following treatment with nobiletin. 24 Nobiletin has also been shown to inhibit growth of metastatic nodules in the lungs of mice via the TGF-β1/SMAD3 pathway 25 and decrease cell migration, angiogenesis, tumor formation, and progression in the bone osteosarcoma cell line U2OS via ERK and JNK pathways.…”

“…23 Multiple experiments showed that nobiletin downregulates CD36, STAT3, pSTAT3, MMPs, and NF-κB proteins, among others in MCF7 cells. 22,23,30 Colony areas were concomitantly increased and decreased with dose in U2OS and MDA-MB-231 cells, respectively, while MCF7 was affected only at the highest concentration used. Previous studies showed that nobiletin-treated breast cancer cells had reduced cell proliferation in largely two-dimensional assays.…”

“…In our study, nobiletin did not alter MCF7 cell migration at the highest concentration tested (50 µM). However, previous studies showed that it reduced cell migration at concentrations of 50 µM, 22 100 µM and 200 µM. 23 Multiple experiments showed that nobiletin downregulates CD36, STAT3, pSTAT3, MMPs, and NF-κB proteins, among others in MCF7 cells.…”

“…Previous studies showed that nobiletin inhibits the proliferation of U2OS, MCF7 and MDA-MB-231 cells 23,26,37 and reduces their migration and invasion. 22,23,26,30 As nobiletin has been posited to be a compound with therapeutic potential, we were interested to determine whether its effects were similar or differed by cell line. First, we assessed changes to cellular migration following nobiletin treatment via wound-healing/scratch assay (Fig.…”

Effects of glycyrrhizin on the pharmacokinetics of nobiletin in rats and its potential mechanism

“…Currently, NBL possesses a variety of physiological activities. It has been reported that NBL can induce apoptosis of human breast cancer cells (Liu et al 2018), inhibit the viability of human renal carcinoma cells (Wei et al 2019) and exert or not exert antileukemic effects (Chen et al 2018). Combination of different drugs can affect the bioavailability of drugs and the anticancer effect.…”