Abstract
We investigated whether licochalcone E (LicE), a phenolic constituent of licorice, inhibits mammary tumor growth and metastasis using animal and cell culture models. 4T1 mammary carcinoma cells were injected into the mammary fat pads of syngeneic BALB/c mice. Starting 7 days after the injection, the mice received LicE (7 or 14 mg/kg body weight/day) via oral gavage for 25 days. LicE suppressed solid tumor growth and lung metastasis, but did not exhibit kidney or liver toxicity. In tumor tissues, LicE treatment induced a reduction in the expression of Ki67, cyclins, and cyclin-dependent kinases and stimulated apoptosis with increased expression of Bax and cleaved caspase-3 but decreased expression of Bcl-2. In addition, LicE decreased expression of CD31, vascular endothelial growth factor (VEGF)-A and C, VEGF-receptor 2, lymphatic vessel endothelial receptor-1, CD45, cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia inducible factor-1α in tumor tissues. In lung tissues, LicE reduced the levels of proinflammatory cytokines and angiogenesis/metastasis-related proteins. In mammary cancer cell cultures, LicE (5-20 μmol/L) dose dependently inhibited cell migration and invasion. LicE inhibited secretion of matrix metalloproteinase-9, urokinase-type plasminogen activator and VEGF-A, and stimulated secretion of tissue inhibitor of metalloproteinase-2 in MDA-MB-231 cells. In addition, LicE inhibited tube formation of vascular endothelial cells. We show that LicE administration suppressed tumor growth and lung metastasis in the mouse model in conjunction with LicE inhibition of cell migration, invasion, and tube formation in vitro. Reduced tumor growth and metastasis in LicE-treated mice may be, at least in part, attributed to reduced inflammation and tumor angiogenesis.
Highlights
Breast cancer is one of the most common malignant diseases and the most aggressive cancer type of women worldwide [1]
Reagents Antibodies against vascular endothelial growth factor (VEGF)-A and C, platelet endothelial cell adhesion molecule (PECAM)-1 (CD31), cyclin-dependent kinase (CDK)2, CDK4, cyclin A, cyclin D1, Bax, Bcl-2, and cleaved caspase-3 were purchased from Santa Cruz Biotechnology
Oral administration of licochalcone E (LicE) inhibits solid tumor growth and lung metastasis in BALB/c mice injected with 4T1 cells
Summary
Breast cancer is one of the most common malignant diseases and the most aggressive cancer type of women worldwide [1]. Despite early detection and apparently complete surgical resection, many patients still die of metastatic cancer that remains undetected at diagnosis [2]. Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/). Metastasis is a complex process that includes the separation of cancer cells from their primary tumor site by breaking through the stromal tissue, transportation through lymphatics or blood vessels, adhesion to the basement membrane, and invasion at the target organ of distant metastasis [reviewed [3]]. Identification of dietary bioactive compounds lacking toxicity and capable of blocking more than one of these processes could be a good strategy to prevent metastasis
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