Glucans as New Anticancer Agents
PETR SIMA1, JOSEF RICHTER2 and VACLAV VETVICKA3
1Department of Immunology, Institute of Microbiology, Prague, Czech Republic;
2Institute of Public Health in Usti nad Labem, Ústí nad Labem, Czech Republic;
3Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, U.S.A.
Abstract
For decades, glucans have been studied for their biological and immunological activities. The scientific community has mainly focused on immune reactions, but other areas, such as cholesterol levels and diabetic retinopathy, have shown the positive effects of glucan supplementation. However, the majority of studies focused on possible cancer suppression, where glucans showed clear and significant effects on numerous types of cancers, leading not only to clinical trials, but to approval as an official drug. The aim of this review is to describe the current knowledge of this field. The use of natural immunomodulators remains one of the primary interests of both the general public and health professionals. In this review we focus on the up-to-date knowledge on the use of glucans in medicine. Throughout history, people have been aware that some mushrooms have healing properties. An ancient text found in India, written more than 5,000 years ago, focuses on the medicinal effects of mushrooms, and a Japanese legend described monkeys without serious diseases after feasting on the mushroom Lentinula edodes. Much later, Japanese interest in chemical components was based on this legend, resulting in development of lentinan. African shamans and Native Americans have used similar knowledge (1). β-1,3-D-Glucans (hereafter referred to as glucans) are natural molecules able to significantly improve our health. They represent highly conserved structures often named pathogen-associated molecular patterns [for review, see Zipfel and Robatzek (2)]. There are many chemically heterogeneous polymers of beta glucose differing in glycosidic bond position. Some have a linear molecule with (1→3)-beta-D-glycosidic linkages, and some have a branched one, with side chains bound by (1→6)-beta-D-glycosidic linkages. All glucans may cause nearly identical immunological responses within multicellular organisms regardless of their origin, structure and water solubility. In addition, they elicit numerous other physiological effects and, therefore, are generally classified as immunomodulators within a large group of so-called biological response modifiers (3-6). Glucans as structural components of fungal, yeast, and seaweed cells are ranked among immuno-stimulants such as endotoxin of Gramnegative microorganisms, muramyldipeptide, zymosan, and polynucleotides. A proper history of polysaccharides considered to be immunomodulators can be traced back almost 80 years when Shear and Turner described a polysaccharide isolated from Serratia marcescens that sometimes caused tumor necrosis (7). In Europe and Northern America, the investigation of polysaccharides in medicine started in the 1960s and 1970s. It was originally based on the immunomodulatory effects of zymosan, which was isolated by Pillemer and Ecker from baker’s yeast, Saccharomyces cerevisiae (8). Zymosan is a mixture of various polysaccharides in which the glucan-rich fraction exerts the main biological activity (8). Various types of glucans have now been isolated which differ in molecular weight, branching, and biological activities. It is important to note that some of these glucans have shown no or very low biological activity (9). Initially, most research studies on glucans focused on the effects on the murine immune system. However, subsequent research has clearly established that glucan has strong immunostimulatory effects in a wide variety of species, including earthworms, bees, shrimp, fish, chicken, rats, rabbits, guinea pigs, sheep, goats, pigs, cows, monkeys, and humans (10-12). It has been concluded that glucans represent unique immunostimulants that are active in every species; it is one of the few immunostimulants active across the evolutionary spectrum (13). Some surprising experiments have even demonstrated that glucan supports plant protection against disease (14, 15). Glucans are considered strong activators of cellular immunity, with macrophages being their most important targets. Originally, glucans were established as playing a role in protection against infection. Since the original study published more than 35 years ago showing possible cancer suppression (16), the antitumor activity of glucans has been established. In fact, numerous animal and human studies have shown glucans to have remarkable activity against a wide variety of tumors (17-21), leading to use of glucan as an official drug (22). Studies focused on mechanism of action have revealed that glucans have strong synergy with naturally occurring anticancer antibodies (19, 23, 24). Glucans have pleiotropic effects on individual branches of the defense reactions. The individual components of the immune system affected by glucans are summarized in Figure 1. Glucans are recognized by various receptors present on membranes of cells such as macrophages, monocytes, dendritic cells, and natural killer cells. The most important receptors are dectin-1 and complement receptor 3 (CR3; CD11b/CD18); additional receptors include toll-like receptor 2 (TOLL2), lactosylceramides, and the scavenger receptor family [for review, see Vetvicka (25)]. Upon binding, various biological processes occur, including direct receptor activation and cellular pathway activation (25).