Chia-Chien Hsieh

Lunasin, a novel seed peptide for cancer prevention

Carcinogenesis is a multistage process derived from a combination of multiple heritable and environmental factors. It has been reported that populations consuming high levels of soybean products have both lower cancer incidence and mortality rates in the western countries. Lunasin is a novel and promising peptide initially discovered in soy and now found in wheat, barley and other seeds. Its cancer-preventive efficacy has been shown in mammalian cells which were induced by chemical carcinogens and viral oncogenes. Moreover, this peptide has been found to prevent skin cancer in a mouse cancer model induced by chemical carcinogens. Its bioavailability after oral administration makes it a perfect candidate as a chemopreventive agent. The purpose of this article is to review the discovery of this seed peptide and the most recent evidence on its possible benefits as an anticancer agent.

Complementary roles in cancer prevention: protease inhibitor makes the cancer preventive peptide lunasin bioavailable.

Background The lower incidence of breast cancer among Asian women compared with Western countries has been partly attributed to soy in the Asian diet, leading to efforts to identify the bioactive components that are responsible. Soy Bowman Birk Inhibitor Concentrate (BBIC) is a known cancer preventive agent now in human clinical trials. Methodology/Principal Findings The objectives of this work are to establish the presence and delineate the in vitro activity of lunasin and BBI found in BBIC, and study their bioavailability after oral administration to mice and rats. We report that lunasin and BBI are the two main bioactive ingredients of BBIC based on inhibition of foci formation, lunasin being more efficacious than BBI on an equimolar basis. BBI and soy Kunitz Trypsin Inhibitor protect lunasin from in vitro digestion with pancreatin. Oral administration of 3H-labeled lunasin with lunasin-enriched soy results in 30% of the peptide reaching target tissues in an intact and bioactive form. In a xenograft model of nude mice transplanted with human breast cancer MDA-MB-231 cells, intraperitoneal injections of lunasin, at 20 mg/kg and 4 mg/kg body weight, decrease tumor incidence by 49% and 33%, respectively, compared with the vehicle-treated group. In contrast, injection with BBI at 20 mg/kg body weight shows no effect on tumor incidence. Tumor generation is significantly reduced with the two doses of lunasin, while BBI is ineffective. Lunasin inhibits cell proliferation and induces cell death in the breast tumor sections. Conclusions/Significance We conclude that lunasin is actually the bioactive cancer preventive agent in BBIC, and BBI simply protects lunasin from digestion when soybean and other seed foods are eaten by humans.

Lunasin, a novel seed peptide, sensitizes human breast cancer MDA-MB-231 cells to aspirin-arrested cell cycle and induced apoptosis

Breast cancer is one of the most common tumors in women of Western countries. The high aggressiveness and therapeutic resistance of estrogen-independent breast tumors have motivated the development of new strategies for prevention and/or treatment. Combinations of two or more chemopreventive agents are currently being used to achieve greater inhibitory effects on breast cancer cells. This study reveals that both aspirin and lunasin inhibit, in a dose-dependent manner, human estrogen-independent breast cancer MDA-MB-231 cell proliferation. These compounds arrest the cell cycle in the S- and G1-phases, respectively, acting synergistically to induce apoptosis. To begin elucidating the mechanism(s) of action of these compounds, different molecular targets involved in cell cycle control, apoptosis and signal transduction have been evaluated by real-time polymerase chain reaction (RT-PCR) array. The cell growth inhibitory effect of a lunasin/aspirin combination is achieved, at least partially, by modulating the expression of genes encoding G1 and S-phase regulatory proteins. Lunasin/aspirin therapy exerts its potent pro-apoptotic effect is at least partially achieved through modulating the extrinsic-apoptosis dependent pathway. Synergistic down-regulatory effects were observed for ERBB2, AKT1, PIK3R1, FOS and JUN signaling genes, whose amplification has been reported as being responsible for breast cancer cell growth and resistance to apoptosis. Therefore, our results suggest that a combination of these two compounds is a promising strategy to prevent/treat breast cancer.

Soybean Peptide Lunasin Suppresses In Vitro and In Vivo 7,12-Dimethylbenz[a]anthracene-Induced Tumorigenesis

Lunasin is a novel peptide identified in soybean and other seeds. This study evaluated the anti-tumorigenic effects of lunasin on 7,12-dimethylbenz(a)anthracene (DMBA) and 3-methylcholanthrene-treated (MCA) fibroblast NIH/3T3 cells. Lunasin significantly inhibited cell proliferation and cancerous foci formation in these 2 chemical carcinogens-treated cells. An in vivo SENCAR mouse model induced with DMBA was used to study the mammary cancer preventive properties of dietary lunasin contained in soy protein. Tumor incidence was 67% and 50%, and the tumor generation was 1.88 ± 0.48 and 1.17 ± 0.17, respectively, for the mice fed control diet and experimental diet obtained after AIN-93G supplementation with lunasin-enriched soy protein concentrate (containing 0.23% lunasin). However, no effects were observed in mice fed AIN-93G supplemented with soy protein concentrate (containing 0.15% lunasin). The data provided illustrate the anticancer potential of lunasin both in vitro and in vivo and supports the recommendation of soy protein as a dietary component that may aid in the prevention of mammary cancer.

Chemopreventive Properties of Peptide Lunasin: A Review

Cancer has become one the most common causes of death in developed countries and has been defined as the medical challenge of our times. Accumulating evidence support the notion that prevention can be a major component of cancer control. Chemoprevention, a relatively new and promising strategy to prevent cancer, is defined as the use of natural and/or synthetic substances to block, reverse, or retard the process of carcinogenesis. Plant-based foods, containing significant amounts of bioactive phytochemicals, may provide desiderable health benefits beyond basic nutrition to reduce the process of cancer. In the last few years, proteins and peptides have become one group of nutraceuticals that show potential results in preventing the different stages of cancer including initiation, promotion, and progression. Lunasin is a 43- amino acid peptide identified in soybean and other plants whose anti-carcinogenic activity has been demonstrated both in in vitro and in vivo assays. Moreover, this peptide has been found to exert anti-inflammatory and antioxidant properties that could contribute to its chemopreventive effects. Lunasins bioactivity and its molecular mechanism(s) of actions are summarized in this review.

Relationship between lunasin's sequence and its inhibitory activity of histones H3 and H4 acetylation

SCOPE Dysfunction of histone acetyltransferases (HATs) or histone deacetylases (HDACs) involved in histones acetylation has been associated with cancer. Inhibitors of these enzymes are becoming potential targets for new therapies. METHODS AND RESULTS This study reports by Western-Blot analysis, that peptide lunasin is mainly an in vitro inhibitor of histone H4 acetylation by P300/cAMP-response element-binding protein (CBP)-associated factor (PCAF), with IC₅₀ values dependent on the lysine position sensitive to be acetylated (0.83 μM (H4-Lys 8), 1.27 μM (H4-Lys 12) and 0.40 μM (H4-Lys 5, 8, 12, 16)). Lunasin is also capable of inhibiting H3 acetylation (IC₅₀ of 5.91 μM (H3-Lys 9) and 7.81 μM (H3-Lys 9, 14)). Studies on structure-activity relationship establish that lunasins sequence are essential for inhibiting H4 acetylation whereas poly-D sequence is the main active sequence responsible for H3 acetylation inhibition. Lunasin also inhibits H3 and H4 acetylation and cell proliferation (IC₅₀ of 181 μM) in breast cancer MDA-MB-231 cells. Moreover, this peptide decreases expression of cyclins and cyclin dependent kinases-4 and -6, implicated in cell cycle pathways. CONCLUSION Results from this study demonstrates lunasins role as modulator of histone acetylation and protein expression that might contribute on its chemopreventive properties against breast cancer.

Lunasin and Bowman-Birk Protease Inhibitor Concentrations of Protein Extracts from Enzyme-Assisted Aqueous Extraction of Soybeans

Lunasin and Bowman-Birk protease inhibitor (BBI) are two soybean peptides to which health-promoting properties have been attributed. Concentrations of these peptides were determined in skim fractions produced by enzyme-assisted aqueous extraction processing (EAEP) of extruded full-fat soybean flakes (an alternative to extracting oil from soybeans with hexane) and compared with similar extracts from hexane-defatted soybean meal. Oil and protein were extracted by using countercurrent two-stage EAEP of soybeans at 1:6 solids-to-liquid ratio, 50 °C, pH 9.0, and 120 rpm for 1 h. Protein-rich skim fractions were produced from extruded full-fat soybean flakes using different enzyme strategies in EAEP: 0.5% protease (wt/g extruded flakes) used in both extraction stages; 0.5% protease used only in the second extraction stage; no enzyme used in either extraction stage. Countercurrent two-stage protein extraction of air-desolventized, hexane-defatted soybean flakes was used as a control. Protein extraction yields increased from 66% to 89-96% when using countercurrent two-stage EAEP with extruded full-fat flakes compared to 85% when using countercurrent two-stage protein extraction of air-desolventized, hexane-defatted soybean flakes. Extruding full-fat soybean flakes reduced BBI activity. Enzymatic hydrolysis reduced BBI contents of EAEP skims. Lunasin, however, was more resistant to both enzymatic hydrolysis and heat denaturation. Although using enzymes in both EAEP extraction stages yielded the highest protein and oil extractions, reducing enzyme use to only the second stage preserved much of the BBI and Lunasin.

Identification of chemopreventive peptide lunasin in some Lupinus species.

Trabajo presentado a la 13th International Lupin Conference celebrada en Poznan (Polonia) del 6 al 10 de junio de 2011.

Lunasin, a New Breast Cancer Chemopreventive Seed Peptide

With a prevalence of about 4.4 million women and a lethality rate of more than 410,000 cases per year, breast cancer is the most common cancer disease and the leading cause of death in women worldwide (Mangiapane et al., 2008). Advances in early detection and improved treatment for breast cancer have led to a steady decrease in the overall breast cancer mortality rate. However, breast cancer remains a significant cause of morbidity and mortality. In general, breast cancer is categorized into the estrogen receptor (ER)–positive type and the ER-negative type, based on the prevalence of ERs within the cell. About 70-80% of all breast cancers are estrogen sensitive and they are treated by conventional procedures including surgery, radiation chemotherapy, and estrogen analogues. Results from clinical trials have demonstrated that it is possible to prevent estrogen-responsive breast cancers by targeting the ER with selective modulators (i.e. tamoxifen, raloxifene, or lasofoxifene) or with aromatase inhibitors (i.e. anastrozole, letrozole, or exemestene). While the ER-positive tumors respond to anti-estrogen therapy and have better prognosis, the ER-negative tumors are more aggressive and resistant to treatments (Uray & Brown, 2006; Li & Brown, 2007; Cuzick, 2008). The high aggressiveness and therapeutic resistance of ER-negative breast tumors have made necessary the development of new and efficient strategies for their prevention and/or treatment. Recently, the World Cancer Research Fund/American Institute for Cancer Research has reported that changes in diet and lifestyle are good strategies for cancer prevention. Evidence based on a systematic review of the published literature has demonstrated benefits of diet modification approach to reduce cancer risk (Greenwald & Dunn, 2009). The rising prevalence of cancer worldwide and the corresponding rise in health care costs is propelling interest among researchers and consumers for multiple health benefits of food compounds, including reduction in cancer risk and modification of tumor behavior (Beliveau, 2007; Kaefer and Milner, 2008). A large number of natural compounds present in the diet have been demonstrated to lower breast cancer risk and sensitize tumor cells to anti-cancer therapies (Kaefer & Milner, 2008; Ramos, 2008; Hauner & Hauner, 2010). Among these dietary compounds, those present in plant foods and collectively termed phytochemicals,

Seed Components in Cancer Prevention

Publisher Summary This chapter summarizes the main components contained in seeds for which cancer-preventive properties have been reported. It has been estimated that 30-40% of all cancers can be prevented by appropriate diet, physical activity, and maintenance of appropriate weight. Epidemiological evidence, cell culture, and animal tumor model studies have demonstrated that a large number of natural compounds present in the diet could lower cancer risk and even sensitize tumor cells in anticancer therapies. Many different seed components play important roles in preventing cancer, especially phenolic compounds or polyphenols. They are formed to protect the plant from photosynthetic stress, reactive oxygen species, wounds, and herbivores. In legumes and cereals, the main polyphenols are flavonoids, phenolic acids, and tannins. The other bioactive phytochemicals with potent cancer-preventive activity are terpenoids. Chemoprevention is a new and promising strategy to prevent cancer by using natural and/or synthetic substances that block, reverse, or retard the process of carcinogenesis. Different mechanisms of action have been reported to be responsible for the anticancer properties of these bioactive compounds. They are important due to their antioxidant and anti-inflammatory activities. Moreover, many of them exert their chemopreventive properties by interfering with multiple cell-signaling pathways, cell proliferation, and apoptosis.