Lunasin natin ang cancer! Lunasin – a novel cancer preventive substance from seeds

Lunasin (from Pilipino word lunas for cure) is a novel cancer preventive peptide (a small protein) that was first discovered in soy and now found in other seeds. Strictly speaking, lunas is not the proper word because lunasin has so far been found to be preventive not curative – but it sounds good anyway! Would iwasanin (from iwasan) be more appropriate? The serendipitous discovery of lunasin in our laboratory provides another explanation for the known anti-cancer properties of soy and other seed crops and opens up the opportunity to develop nutraceuticals and pharmaceuticals based on lunasin technology. It is not unusual that many profound discoveries were made serendipitously – without the intention of making the discoveries. Lunasin is such an example.

Many years ago, my laboratory initiated a project on enhancing the nutritional of soy protein and other legumes through bioengineering. This requires increasing the level of methionine, the essential amino acid, which is most limiting in soy and other legumes, including mung bean. The strategy is quite straightforward: clone a gene coding for methionine-rich protein (MRP) and over-express the gene in soy or any target legume. We were faced with two choices for the source of the MRP gene – obtain it from other plants or from soy itself. I made the fateful decision to clone the MRP gene from soy itself, which eventually led to the discovery of lunasin as a cancer preventive agent. Had I not made this decision, I would not be writing about lunasin now – but who knows? At that time, there were two other groups that made the other choice – one group (Pioneer Hybrid International Inc.) cloned the MRP gene from Brazil nut which has a high methionine content and over-expressed it in soy, and the other (Dr. T.J. Higgins at Division of Plant Industry, Canberra, Australia) chose to clone the MRP gene from sunflower seed and over-express it in lupine, a cover crop used to feed sheep in Australia. The Brazil nut MRP in transgenic soy turned out to be allergenic to humans and led to the termination of the project. The Australian project is successful, in fact resulting in increased yield of wool for sheep fed on the transgenic lupines.

The choice to clone the MRP gene from soy is based on the hypothesis that there must be non-abundant MRPs in soy because most of the proteins in soy seed are notoriously low in methionine and therefore, there must be other MRPs that contribute to the overall methionine content of soy protein but they are non-abundant. The process of cloning the MRP gene turned out to be not easy, taking about four years, two graduate students and a postdoctoral scientist. One of the graduate students is a Filipina (now Dr. Jamie Revilleza from UPLB), and the postdoctoral scientist is another Filipino from UPLB (Dr. Alfredo Galvez). Dr. Revilleza contributed to the purification of the MRP from soy that eventually led to the cloning of the gene, and Dr. Galvez took over the project and discovered the anti-mitotic effect of the lunasin gene when transfected into mammalian cells and the cancer preventive effect of the lunasin peptide. While it was not by design that the major contributors to lunasin discovery were both Filipinos, it is a source of pride to point this out.

Since its discovery in 1999, lunasin has been shown to be effective in preventing the transformation of normal cells to cancer cells caused by chemical carcinogens as well as cancer-causing agents from viruses such as the one known to cause cervical cancer in women. This is relevant to the Philippines, other Asian countries and other developing countries all over the world where cervical cancer is the most prevalent cancer among women. Indeed, there is a plan to conduct clinical trials on cervical cancer in the Philippines when the proper time comes.

In the first animal model, lunasin was found to prevent skin cancer in mice when applied topically. It is likely then that the first commercial application of lunasin would be in skin cancer or at least in the formulation of over-the-counter "cosmeceuticals" to maintain a healthy skin. Topical application to prevent cervical cancer is also a likely application in the immediate future.

Since lunasin is a small protein, it is expected to be digested when we eat soy. We now have evidence that lunasin is protected from digestion by naturally present protease inhibitors in soy and other seeds.

The way lunasin works still needs to be elucidated further. However, accumulated evidence points to a unique and novel "epigenetic" mechanism – lunasin selectively kills cells that are being attacked by carcinogenic agents while leaving other cells unharmed by interfering with the unfolding of the chromosome that is necessary for cell proliferation. This unique epigenetic mechanism lends scientific legitimacy to lunasin and makes it different from currently studied soy chemopreventive agents such as phenolics and isoflavones that function as antioxidants and phystoestrogens.

Lunasin may play a key and fascinating role during seed development. Seed development in angiosperm is characterized by three major stages. First, there is rapid cell division and differentiation; secondly, cell division stops and the cells enlarge, accompanied by synthesis of DNA, lipids, proteins and carbohydrates; and finally, the seed dries up. We believe that lunasin could be an effector molecule that allows the arrest of cell division to initiate the second stage. The hypothesis remains to be tested and proven.

Lunasin technology, because of its promise, is protected by numerous patents owned by the University of California at Berkeley, a necessary first step in its commercial development. Patents have been filed and granted in the US, Canada, Japan, European Union and other countries. A start-up biotech company, FilGen BioSciences Inc., has been formed and granted a license to commercialize lunasin. It is noteworthy that the initial investors in the company are Filipino-Americans.

Lunasin’s story is a fascinating one and continues to be so. Its discovery is serendipitous, its applications myriad, and its mechanism of action novel.

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Ben O. de Lumen, Ph.D., is a professor at the Department of Nutritional Sciences and Toxicology, University of California at Berkeley, CA. He is a member of the Philippine Academy of Science and Engineering. E-mail him at [email protected].