Efficacy and mechanism of action of Deguelin in suppressing metastasis of 4T1 cells

Abstract

Cancer related deaths in breast cancer patients are due to metastasis of the disease. Murine 4T1 cells (Murine mammary cancer cell line developed from 6-thioguanine resistant tumor) provide an excellent research tool for metastasis related studies because these cells are highly aggressive and readily metastasize to the lungs. In this study we determined the effect of Deguelin on in vivo/vitro growth and metastasis of 4T1 cells. Deguelin inhibited the in vitro growth of 4T1 cells in a time and dose dependent manner accompanied with reduced nuclear PCNA immunostaining. In cells treated with Deguelin, reduced expression of nuclear c-Met, and its downstream targets such p-ERK and p-AKT was observed. Deguelin reduced the cell migration in 4T1 cells as determined by scratch wound assay. Combined treatment with Deguelin + ERK or PI3K/AKT inhibitor had no additional effect on cell migration. These results indicated that the action of Deguelin on cell migration may be mediated by AKT and ERK mediated signaling pathways. In vivo, Deguelin treatment significantly inhibited growth of 4T1 cells. Deguelin also reduced the occurrence of metastatic lung lesions by 33% when cells were injected intravenously into Balb/c female mice. There was no difference in the body weight as well as liver and spleen weights between vehicle treated control and Deguelin treated animals indicating that Deguelin was nontoxic at the dose used in the present study. These results provide rationale for developing Deguelin as a chemotherapeutic agent for triple negative breast cancer patients.

Deguelin inhibits proliferation and migration of human pancreatic cancer cells in vitro targeting hedgehog pathway

“…Several studies have already demonstrated its excellent potential as an anticarcinogenic and antiproliferative agent against various malignant tumors including gastric, lung and breast carcinoma, by targeting apoptosis, cell cycle arrest and anti-angiogenesis (5-7). Deguelin also exhibits effects of anti-metastasis (7,8). It inhibits cancers through a number of pathways, including the PI3K-Akt, HIF-1-VEGF, IKK-IκBα-NF-κB, EMT and AMPK-mTOR-survivin pathways (4-7).…”

Effect of flavonoid compounds extracted from Iris species in prevention of carbon tetrachloride-induced liver fibrosis in rats

“…Studies have shown that flavonoid compounds can protect the liver through multiple pathways, such as by preventing high liver iron levels, inhibiting lipid peroxidation and hepatic protein oxidation, and facilitating iron excretion (Feher and Lengyel, 2012;Sak, 2014). Additionally, flavonoid compounds have a stronger anti-oxidative activity than vitamin C and vitamin E (Mehta et al, 2013). In contrast, flavonoid compounds can exert their protective role by regulating cell apoptosis; these compounds can inhibit normal hepatic cell apoptosis while accelerating apoptosis of tumor cells and necrotic hepatic cells.…”

Inositol 1, 4, 5-trisphosphate-dependent nuclear calcium signals regulate angiogenesis and cell motility in triple negative breast cancer

“…4T1 cells (American Type Culture Collection—ATCC), a widely used triple negative breast cancer cell line [18,19] and a murine model for stage IV human breast cancer, were grown at 37°C with 5% CO 2 in RPMI-1640 supplemented with 10% fetal bovine serum (FBS), 100 units/mL penicillin and 50 g/mL streptomycin, all from GIBCO (Grand Island, NY). MDA-MB-231 and MDA-MB-468, also triple negative breast cancer cell lines, however, derived from human breast tumors, were purchased from ATCC and cultivated at 37°C with 5% CO 2 in DMEM medium supplemented with 10% FBS, 100 units/mL penicillin and 50 g/mL streptomycin.…”