title: Luteolin suppresses development of medroxyprogesterone acetate-accelerated 7,12-dimethylbenz(a)anthracene-induced mammary tumors in Sprague-Dawley rats.
abstract: Postmenopausal women undergoing hormone-replacement therapy containing both progestins and estrogens are at an increased risk of developing breast cancer compared with women taking estrogen alone. We recently demonstrated that medroxyprogesterone acetate, a progestin commonly used for hormone-replacement therapy, accelerates development of mammary carcinogenesis in 7,12-dimethylbenz(a)anthracene‑treated Sprague-Dawley rats. Synthetic antiprogestins used to block the deleterious effects of progestins, are themselves associated with toxic side-effects. In order to circumvent this, we used the aforementioned model to identify less toxic natural compounds that may prevent the development of progestin-accelerated tumors. Luteolin, a naturally-occurring flavonoid commonly found in fruits and vegetables, has previously been shown to possess anticancer properties. In our studies, both low (1 mg/kg) and high (25 mg/kg) doses of luteolin significantly suppressed progestin-dependent increases in tumor incidence, while increasing tumor latency and reducing the occurrence of large (>300 mm3) mammary tumors. However, an intermediate dose of luteolin (10 mg/kg), while suppressing the development of large tumors, did not affect either tumor incidence or latency. Immunohistochemical analysis of tumor tissues revealed that all concentrations of luteolin (1, 10, and 25 mg/kg) significantly reduced levels of VEGF within tumors. The suppressive effects of luteolin on tumor incidence and volume, together with its ability to reduce VEGF and blood vessels, persisted even after treatment was terminated. This suggests that luteolin possesses anti‑angiogenic properties which could mechanistically explain its capacity to control tumor progression. Thus luteolin may be a valuable, non-toxic, naturally-occurring anticancer compound which may potentially be used to combat progestin-accelerated mammary tumors.
authors.affiliation: Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Cook
authors.affiliation: Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Benford
authors.initials: B
authors.lastname: Mafuvadze
authors.affiliation: IDEXX BioResearch, Columbia, MO 65202, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Besch-Williford
authors.affiliation: Agriculture Experiment Station, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Ellersieck
authors.affiliation: Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Sandy
authors.initials: S
authors.lastname: Goyette
authors.affiliation: Department of Biomedical Sciences and Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO 65211, USA.
authors.forename: Salman M
authors.initials: SM
authors.lastname: Hyder
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D005260:Female; D007150:Immunohistochemistry; D047311:Luteolin / Q000494:pharmacology*; D008325:Mammary Neoplasms, Experimental / Q000473:pathology*; D017258:Medroxyprogesterone Acetate / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D015127:9,10-Dimethyl-1,2-benzanthracene; D017258:Medroxyprogesterone Acetate; D047311:Luteolin