Micronutrient synergy—a new tool in effective control of metastasis and other key mechanisms of cancer

A. Niedzwiecki M. W. Roomi T. Kalinovsky M. Rath Consumption of a plant-based diet has been associated with prevention of the development and progression of cancer. We have developed strategies to inhibit cancer development and its spread by targeting common mechanisms used by all types of cancer cells that decrease stability and integrity of connective tissue. Strengthening of collagen and connective tissue can be achieved naturally through the synergistic effects of selected nutrients, such as lysine, proline, ascorbic acid and green tea extract (NM). This micronutrient mixture has exhibited a potent anticancer activity in vivo and in vitro in a few dozen cancer cell lines. Its anti-cancer effects include inhibition of metastasis, tumor growth, matrix metalloproteinase (MMP) secretion, invasion, angiogenesis, and cell growth as well as induction of apoptosis. Many cancers are often diagnosed at later stages, when metastasis has occurred, which standard treatment has been unable to control. Our studies on NM effects on hepatic and pulmonary metastasis demonstrated profound, significant suppression of metastasis in a murine model. Evaluation of effects of NM on xenografts in murine models demonstrated significant reduction in tumor size and tumor burden in all human cancer cell lines tested. In vitro studies demonstrated that NM was very effective in inhibition of cell proliferation (by MTT assay), MMP secretion (by gelatinase zymography), cell invasion (through Matrigel), cell migration (by scratch test), induction of apoptosis (by live green caspase) and induction of pro-apoptotic genes in many diverse cancer cell lines. - In 2009, there were 562,340 cancer deaths overall, including 159,390 deaths from lung cancer; 49,920 from cancer of the colon/rectum; 40,610 from female breast cancer; 35,240 deaths from cancers of the pancreas; and 27,360 from prostate cancer. Despite extensive use of conventional therapies, cancers such as liver, intrahepatic bile duct, esophageal, and pancreatic continue to increase [1]. Furthermore, cancers are often diagnosed at a later stage, when metastasis has occurred, which standard treatment has been unable to control. Standard cancer treatments, which have been largely unsuccessful, generally involve a combination of surgery, multiple chemotherapeutic agents, and ionizing radiation. Evaluation of clinical trials conducted between 1990 and 2004 on 22 types of cancer showed that chemotherapy could increase the chance of 5-year survival by merely 2.1% [2]. At the same time, it is not effective in treating melanoma, uterine, prostate, and kidney cancers. The main reasons behind disappointing outcomes of chemotherapy are its severe toxicity, immune involvement, and genotoxicity, giving rise to new cancers, as well as development of drug resistance by cancer cells. In addition to being unsuccessful in treating cancer, standard cancer treatments are associated with high costs, which have led to the immense increased cost of healthcare. Thus, there is a need for defining new biological targets and non-toxic solutions. 1.1 Natural approaches in cancer therapy Numerous studies indicate that consumption of a plantbased diet has preventive effects on cancer development and its progression [3, 4]. Many natural compounds such as herbal extracts, vitamins (i.e., vitamin C) and micronutrients have been used in cancer treatment; however, the application of most of natural approaches have been largely based on traditional use and personal experiences with no clear understanding of their cellular targets and mechanisms of action. Research in the area of natural health has been limited and progress slow due to lack of funding for investigations of natural compounds, as they are not patentable and thus would result in low profits. Since 90% of cancer deaths occur secondary to metastasis, any successful anti-cancer treatment has to target this stage of cancer development. Dr. Rath and his colleagues have paved a new direction in the therapeutic use of micronutrients to control cancer growth and metastasis by targeting common pathomechanisms involved in growth and invasion for all types of cancer. A major breakthrough by Dr Rath proposed that collagen stability is the most effective and universal approach to controlling cancer [5]. In this aspect, controlling matrix proteolytic degradation and enhancing extracellular matrix (ECM) structure and its integrity are key steps towards curbing cancer invasiveness and tumor growth. Studies by Almholt et al. [6] have demonstrated limited metastasis in serine (u-PA) deficient mouse model. Also highly metastatic cancer cells secrete higher amounts of matrix metalloproteinases (MMPs) than do poorly metastatic cells, demonstrating that the invasive and metastatic abilities of these cancer cells correlate with an ability of these enzymes to degrade basement membranes [7, 8]. 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. A major structural protein for ECM and basement membrane is Type IV collagen. Therefore, type IV collagenases MMP-2 (72-kd gelatinase A) and MMP-9 (92-kd gelatinase B) have been the focus of research, especially since MMP-2 and MMP-9 expression is associated with cancer cell invasion and is elevated in a variety of malignancies [9, 10]. A significant association has been reported between tumor aggression and increased levels of MMP-2 and MMP-9 in many experimental and clinical studies [11, 12]. The activity of MMPs on the degradation of the ECM 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 [8, 12]. 1.2 Novel approach to cancer through nutrient synergy Rath and Pauling [5] suggested targeting plasmin-mediated connective tissue degradation as a universal approach to controlling common pathomechanisms of cancer. They proposed the use of nutritional components, such as vitamin C and lysine and lysine analogs. Lysine interferes with the activation of plasminogen into plasmin by tissue plasminogen activator by binding to plasminogen active sites, thereby affecting the plasmin-induced MMP activation cascade [5]. Our subsequent studies confirmed the approach described by Rath and Pauling [5] 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 [13, 14]. Furthermore, NM demonstrated significant antiangiogenic activity utilizing the chorioallantoic membrane assay in chick embryos and bFGF-induced vessel growth in C57BL/6 J female mice in the mouse Matrigel plug (...truncated)