Cancer

Comparative Effects of EGCG, Green Tea, and a Nutrient Mixture on the Patterns of MMP-2 and MMP-9 Expression in Cancer Cell Lines

M.W. Roomi, J.C. Monterrey, T. Kalinovsky, M. Rath and A. Niedzwiecki
Dr. Rath Research Institute, 1260 Memorex Drive, Santa Clara, CA 95050

Onc Rep 2010, 24: 747-757

Abstract
Type IV collagenase matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, have been found to promote invasion and metastasis of malignant tumors. Extracellular matrix (ECM) degradation by MMPs and increased expression of MMPs in cancer cells and tumor microvascular endothelial cells make MMPs an attractive target for cancer. Focused on a common pathomechanism of cancer growth and invasion, the disintegration of connective tissue, we used natural approaches to increase the integrity and strength of connective tissues. Utilizing the principle of nutrition synergy, we developed a novel micronutrient mixture (NM) containing lysine, proline, ascorbic acid, and green tea extract. This study evaluates the potency of the components EGCG and green tea extract independently compared to that of NM on modulation of patterns of MMP-2 and MMP-9 expression in four cancer cell lines expressing MMP-2, MMP-9 or both. Human fibrosarcoma (HT-1080), hepatocellular carcinoma (SK-Hep-1), glioblastoma (T-98G), uterine leiomyosarcoma (SK-UT-1) cell lines were obtained from ATCC and grown in minimum essential medium (MEM) supplemented with 10% FBS, penicillin (100 U/ml) and streptomycin (100 mg/ml) in 24-well tissue culture plates. At near confluence, the cells were treated with agents dissolved in media and tested at concentrations indicated in triplicate at each dose. Cells were also treated with PMA 100 ng/ml to study enhanced expression of MMP-9. MMP expression was assessed by gelatinase zymography, Fibrosarcoma and hepatocellular carcinoma cells expressed both MMP-2 and MMP-9. Glioblastoma cells expressed MMP-2 and PMA treatment induced MMP-9 expression. Uterine leimyosarcoma cells expressed no MMPs but PMA induced MMP-9. NM was the most potent dose-dependent inhibitor of MMPs, followed by green tea extract and EGCG. In conclusion, these results suggest the enhanced efficacy of nutrients working in synergy to modulate complex pathways such as MMP expression.

Key Words:
EGCG, green tea, nutrient mixture, MMP-2, MMP-9

 

Attachments:
Synergy_OR.pdf [ ] 482 Kb

 

Distinct patterns of matrix metalloproteinase-2 and -9 expression in normal human cell lines

M.W. Roomi, J.C. Monterrey, T. Kalinovsky, M. Rath, A. Niedzwiecki
Oncology Reports 2009; 21(3): 821-826

Invasion of surrounding tissues by malignant cells is a complex process mediated by the matrix degrading enzymes. In many solid tumors, the expression of MMPs, especially MMP-2 and MMP-9, is higher in stromal cells than in the tumor cells, suggesting stromal cells as the major source of these enzymes. Cytokines and signal transduction pathways, including those activated by phorbol 12-myristate 13-acetate (PMA), regulate the expression of MMPs. The aim of this study was to examine the pattern of MMP-2 and MMP-9 expression in human normal cells and in PMA-treated cells to determine if specific patterns of expression were associated with tissues of different origin.

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Patterns of MMP-2 and MMP-9 expression in human cancer cell lines

M.W. Roomi, J.C. Monterrey, T. Kalinovsky, M. Rath and A. Niedzwiecki
Oncology Reports 2009, 21: 1323-1333

Abstract
MMP-2 and MMP-9 secretion is elevated in several types of human cancers and their elevated expression has been associated with poor prognosis. Expression of MMPs is highly regulated by cytokines and signal transducation pathways, including those activated by phorbol 12-myristate 13-acetate (PMA). The aim of this study was to examine the effect of PMA on MMP-2 and MMP-9 secretion in 42 different human cancer cell lines, selected on the basis of their organ malignancies. They were cultured in the recommended media supplemented with 10% FBS and antibiotics in 24-well tissue culture plates.

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Antiangiogenic properties of a nutrient mixture in a model of hemangioma

M.W. Roomi, T. Kalinovsky, A. Niedzwiecki, M. Rath
Experimental Oncology 2009; 31(4): 214-219

Abstract:
The pathogenesis of hemangiomas is still largely unknown and the current therapy, such as systemic corticosteroid, vincristine, and interferon-alpha, is toxic and remains unsatisfactory. A nutrient mixture (NM) containing lysine, proline, ascorbic acid and green tea extract has shown significant anti-angiogenic and anti-tumor effect against a number of cancer cell lines. Using a mouse hemangioendothelioma model, we investigated the efficacy of NM. We also tested the effect of NM in vitro, evaluating viability, MMP secretion, invasion, morphology and apoptosis.

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A novel mixture containing ascorbic acid, lysine, proline, and green tea extracts inhibits critical parameters in angiogenesis

M.W. Roomi, V. Ivanov, T. Kalinovsky, A. Niedzwiecki, M. Rath
In Anti-Angiogenic Functional and Medicinal Foods, 2007, Losso JN, Shahidi F, Bagchi D (eds), CRC Press, Boca Raton, London, New York, 561-580.

Angiogenesis, the formation of new capillaries from existing blood vessels, is necessary for tumor growth and metastasis to distal organs. MMPs have been recognized as critical to this process secondary to their ability to digest basement membrane and ECM components. The prevention of ECM degradation through the inhibition of MMP activity and increasing its integrity and strength has been shown to be a promising therapeutic approach to block the invasion that occurs during angiogenesis. We developed a novel formulation of lysine, proline, ascorbic acid and green tea extract (NM) which has shown significant anti-cancer activity against a number of cancer cell lines. Our objective was to determine whether NM exhibits anti-angiogenic and antimetastatic effects using in vitro and in vivo experimental models. Since angiogenesis depend on interaction between tumor and endothelial cells, the present study was aimed to determine the effect of NM on both these cells types.

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