Anticancer Effects of a Micronutrient Mixture on Melanoma – Modulation of Metastasis and Other Critical Parameters

Melanoma causes the most skin cancer-related deaths, due to metastasis to other areas of the body, such as lymph nodes, lungs, liver, brain or bone. Though often curable in its early stages, metastatic malignant melanoma is an extremely aggressive cancer with no current viable treatment. Thus, any successful treatment for melanoma has to target metastasis. Invasion of host tissues by cancer cells requires alteration of cancer cell adhesion, cell migration and proteolytic degradation of the extracellular matrix (ECM) (Fidler, 1990). Dr. Rath proposed that optimizing the stability and structure of the ECM and controlling its proteolytic degradation would be the most effective and universal approach to controlling cancer invasiveness and tumor growth (Rath & Pauling, 1992). Degradation of the extracellular matrix (ECM) by matrix metalloproteinases (MMPs) plays a critical role in the formation of tumors and metastasis and has been found to correlate with the aggressiveness of tumor growth and invasiveness of the cancer (Fidler, 1990; Duffy, 1992; Stetler-Stevenson, 2001). Since this process is involved not only in metastasis, but also in angiogenesis and tumor growth, control of proteolytic activity of ECM provides an opportunity to modulate key common aspects of malignancy. Rath and Pauling suggested the use of nutritional components, such as vitamin C and lysine and lysine analogues to target plasmin-mediated connective tissue degradation as a universal approach to controlling common pathomechanisms of cancer (Rath & Pauling, 1992). Lysine interferes with the activation of plasminogen into plasmin by tissue plasminogen activator (tPA) by binding to plasminogen active sites, thereby affecting the plasmin-induced MMP activation cascade (Rath & Pauling, 1992). Our subsequent studies confirmed this approach and resulted in identifying a novel formulation composed of lysine, ascorbic acid, proline and green tea extract and other micronutrients (NM) which has shown significant anticancer activity against a large number (~40) of cancer cell lines, blocking cancer growth, tissue invasion and MMP expression both in vitro and in vivo (Roomi et al., 2010). Furthermore, NM demonstrated significant antiangiogenic activity utilizing the chorioallantoic membrane (CAM) assay in chick embryos and bFGF-induced vessel growth in C57BL/6J female mice in the mouse Matrigel plug assay (Roomi et al, 2005). In addition, in vitro, NM decreased the expression of pro-angiogenic factors of VEGF, angiopoietin-2, bFGF, PDGD and TDGβ-1 by U2OS cells (Roomi et al., 2005).