Inhibitory effect of a mixture containing ascorbic acid, lysine, proline and green tea extract on critical parameters in angio..

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Oncol Rep. 2005 Oct;14(4):807-15.

Inhibitory
effect of a mixture containing ascorbic acid, lysine, proline and green
tea extract on critical parameters in angiogenesis.

Roomi MW, Roomi N, Ivanov V, Kalinovsky T, Niedzwiecki A, Rath M.
 
Matthias Rath Research Institute, Cancer Division, 1260 Memorex Drive, Santa Clara, CA 95050, USA.

 
Degradation
of extracellular matrix (ECM) is a hallmark of tumor invasion,
metastasis and angiogenesis. Based on the Rath multitargeted approach
to cancer using natural substances to control ECM stability and
enhancing its strength, we developed a novel formulation (NM) of
lysine, proline, ascorbic acid and green tea extract that has shown
significant anti-cancer activity against a number of cancer cell lines.

 
The aim of the present study was to determine whether NM exhibits
anti-angiogenic and anti-metastatic effects using in vitro and in vivo
experimental models. Angiogenesis was measured using a chorioallantoic
membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in
C57BL/6J female mice. To determine the in vivo effect of NM on the
tumor xenograft growth, male nude mice were inoculated with 3 x 10(6)
MNNG-HOS cells. Control mice were fed a mouse chow diet, while the test
group was fed a mouse chow diet supplemented with 0.5% NM for 4 weeks.

 
In vitro studies on cell proliferation (MTT assay), MMP expression
(zymography) and Matrigel invasion were conducted on human osteosarcoma
U2OS, maintained in McCoy medium, supplemented with 10% FBS, penicillin
and streptomycin in 24-well tissue culture plates and tested with NM at
0, 10, 50, 100, 500, and 1000 microg/ml in triplicate at each dose. NM
at 250 microg/ml caused a significant (p<0.05) reduction in
bFGF-induced angiogenesis in CAM.
NM inhibited tumor growth of
osteosarcoma MNNG-HOS cell xenografts in nude mice by 53%; furthermore,
tumors in NM-treated mice were less vascular and expressed lower levels
of VEGF and MMP-9 immunohistochemically than tumors in the control
group. In addition, NM exhibited a dose-dependent inhibition of
osteosarcoma U2OS cell proliferation (up to 60% at 1000 microg/ml),
MMP-2 and -9 expression (with virtual total inhibition at 500 microg/ml
NM), and invasion through Matrigel (with total inhibition at 100
microg/ml NM). Moreover, NM decreased U2OS cell expression of VEGF,
angiopoietin-2, bFGF, PDGF and TGFbeta-1.
These results together with
our earlier findings suggest that NM is a relatively non-toxic
formulation, which inhibits growth, invasion, metastasis, and
angiogenesis of tumor cells.