Anticancer effects of the flavonoid diosmetin on cell cycle progression and proliferation of MDA-MB 468 breast cancer cells due to CYP1 activation

Abstract

Abstract. Flavonoids constitute a large class of polyphenolic compounds with cancer preventative properties. We have examined the ability of the natural flavone diosmetin to inhibit proliferation of breast adenocarcinoma MDA-MB 468 and normal breast MCF-10A cells and found that this compound is selective for the cancer cells with slight toxicity in the normal breast cells. Diosmetin was metabolised to the structurally similar flavone luteolin in MDA-MB 468 cells, whereas no metabolism was seen in MCF-10A cells. Diosmetin caused G 1 arrest at 10 μM in MDA-MB 468 cells after 48-h treatment whereas this effect was not observed in MCF-10A cells. We suggest that diosmetin exerts cytostatic effects in MDA-MB 468 cells, due to CYP1A1 and CYP1B1 catalyzed conversion to the flavone luteolin.

Screening of flavonoid aglycons’ metabolism mediated by the human liver cytochromes P450

“…This reaction is catalyzed by human liver microsomes (HLM), and since less than 10 % (m/m) of the metabolite is produced in comparison to the substrate concentration, the metabolism of diosmetin was not further characterized. The results obtained in this study agree with those previously published by Androutsopoulos et al who conducted in vitro experiments with recombinant cytochrome P450 and MCF-7 breast cancer cell lines (10) as well as cell lines of breast adenocarcinoma MDA-MB 468 and normal breast tissue MCF-10A (29) showing that the main route of diosmetin metabolism was the same as suggested in this study. Authors of aforementioned studies (10,29) further determined that CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A5 are not responsible for this reaction and that the major role in the oxidative metabolism of diosmetin is attributed to CYP1A2 and, to a lesser extent, CYP3A4.…”

Diosmetin inhibits cell proliferation and promotes apoptosis through STAT3/c-Myc signaling pathway in human osteosarcoma cells

“…It is rich in citrus fruits, olive leaves and extracts from common herbs in southern China with a variety of functions such as scavenging free radicals, anti-inflammatory and anti-oxidative stress [ 13 – 15 ]. Recently, it is shown that diosmetin has anti-tumor effect by inhibiting the cell proliferation, inducing cell apoptosis and regulating cell cycle on breast cancer cells, liver cancer cells, colon cancer cells, leukemia cells and other tumors, indicating it is a potential promising treatment for cancers [ 17 , 18 , 40 , 41 ]. Studies have shown that diosmetin exerts anti-tumor effect through a variety of mechanisms and the mechanisms are varied in different tumors.…”

“…Studies have shown that diosmetin exerts anti-tumor effect through a variety of mechanisms and the mechanisms are varied in different tumors. For example, diosmetin inhibited the growth of MDA-MB468 breast cancer cells by the activation of CYP1A1 and CYP1B1, which led to the cell cycle arrested in G1 phase, but it was non-cytotoxicity to normal breast cells MCF-10A, suggesting that the use of diosmetin in cancer treatment may be safe and selectively cytotoxic to cancer cells [ 17 ] While in human liver cancer HepG-2 cells, diosmetin induced apoptosis by up-regulating Bax, cleaved-caspase-3, cleaved-caspase-8 and cleaved-caspase-9, and induced G2/M cell cycle arrest by up-regulating the expression levels of p21 and p53, and down-regulated cyclin B, CDK-1 [ 42 ]. In addition, diosmetin inhibited the activity of cytochrome P450 enzymes, regulated the TGF-β signal pathway by up-regulating the expression of p53 and down-regulating the protein expression of Bcl-2, TGF-β, TβR-II, Smad-3, p-Smad2/3, and induce HepG2 apoptosis in liver cancer [ 43 ].…”

“…Notably, diosmetin did not show any detectable adverse effects in an acute toxicity study, suggesting that it may be safe for use in the human body [ 16 ]. In recent years, several studies found that diosmetin exerted antitumor effect on liver cancer and breast cancer through inhibiting tumor proliferation, inducing tumor cell apoptosis and regulating tumor cell cycles [ 17 , 18 ]. While its antitumor role in osteosarcoma cells remained unknown.…”

Assessing the Anti-cancer Therapeutic Mechanism of a Herbal Combination for Breast Cancer on System-level by a Network Pharmacological Approach

“…Isorhamnetin is known to inhibit cell proliferation and induce apoptosis in human BC via the regulation of MAPK and PI3K/Akt pathways (56). Moreover, kaempferol, diosmetin, mairin and quercetin have been shown to function by inducing cell cycle arrest of human BC cells (57,58,65,66). Decursin inhibits Pin1 activation and promotes its association with p53 (67).…”