Apigenin Prevents Development of Medroxyprogesterone Acetate-Accelerated 7,12-Dimethylbenz(a)anthracene-Induced Mammary Tumors in Sprague–Dawley Rats

Abstract

The use of progestins as a component of hormone replacement therapy has been linked to an increase in breast cancer risk in postmenopausal women. We have previously shown that medroxyprogesterone acetate (MPA), a commonly administered synthetic progestin, increases production of the potent angiogenic factor vascular endothelial growth factor (VEGF) by tumor cells, leading to the development of new blood vessels and tumor growth. We sought to identify nontoxic chemicals that would inhibit progestin-induced tumorigenesis. We used a recently developed progestin-dependent mammary cancer model in which tumors are induced in Sprague-Dawley rats by 7,12-dimethylbenz(a)anthracene (DMBA) treatment. The flavonoid apigenin, which we previously found to inhibit progestin-dependent VEGF synthesis in human breast cancer cells in vitro, significantly delayed the development of, and decreased the incidence and multiplicity of, MPA-accelerated DMBA-induced mammary tumors in this animal model. Whereas apigenin decreased the occurrence of such tumors, it did not block MPA-induced intraductal and lobular epithelial cell hyperplasia in the mammary tissue. Apigenin blocked MPA-dependent increases in VEGF, and suppressed VEGF receptor-2 (VEGFR-2) but not VEGFR-1 in regions of hyperplasia. No differences were observed in estrogen or progesterone receptor levels, or the number of estrogen receptor-positive cells, within the mammary gland of MPA-treated animals administered apigenin, MPA-treated animals, and placebo treated animals. However, the number of progesterone receptor-positive cells was reduced in animals treated with MPA or MPA and apigenin compared with those treated with placebo. These findings suggest that apigenin has important chemopreventive properties for those breast cancers that develop in response to progestins.

Apigenin Induces Apoptosis and Blocks Growth of Medroxyprogesterone Acetate-Dependent BT-474 Xenograft Tumors

“…Similar observations were made by Mafuvadze et al [20] in DMBA-induced progestin-accelerated rat mammary tumors and by Gupta et al [52], who suggested that apigenin may exert different effects on prostate cancer cells than on normal cells. By virtue of its ability to selectively induce apoptosis in rapidly growing breast cancer cells, while having no effect on normal mammary cells, apigenin would seem to be an extremely promising chemotherapeutic agent.…”

“…As previously noted in the rat model for DMBAinduced MPA-accelerated mammary gland tumors [20], (Fig. 3), suggesting that apigenin specifically inhibits proliferation of tumor cells.…”

“…We previously showed that apigenin prevents and/or delays the appearance of medroxyprogesterone acetate (MPA)-dependent 7, 12-dimethylbenz (a) anthracene (DMBA)-induced tumors in vivo [20]. In the present study, we demonstrate that apigenin inhibits the progression and development of MPA-dependent BT-474 xenograft tumors in nude mice via a mechanism which involves apoptosis of proliferating human breast cancer cells.…”

“…In a previous study, we showed that apigenin reduces the frequency of DMBA-induced, progestin-accelerated mammary tumors in rats [20]. The present study examines the effect of apigenin on growth and progression of progestin-dependent BT-474 xenograft tumors in nude mice.…”

Anti-inflammatory and acute toxicity evaluation of aqueous infusion extract obtained from aerial parts of <i>Marrubium deserti</i> de Noé growing in Algeria

“…Indeed, the HPLC profile obtained from the aqueous extract of M. deserti (Figure 2), showed the apigenin as a free flavone, which may explain the high anti-inflammatory effect of the aqueous extract of aerial parts of M. deserti. Works of Mafuvadze et al (2011) suggested that apigenin has important chemopreventive properties for breast cancer, through its anti-inflammatory activity. In conclusion, this study showed that the aqueous infusion extract of M. deserti possess a good anti-inflammatory activity which is confirmed by the inhibition of carrageenin-induced paw oedema.…”