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Avemar (Wheat Germ Extract) in Cancer Prevention and Treatment
Abstract
Many healthy foods are derived from wheat germ. The molecular composition of these products, however, greatly differs as shown by normal-phase HPLC-mass spectrometry analysis; thus, experimental data obtained by one of them is not necessarily true for the other. Avemar is a nontoxic wheat germ extract registered as a special nutriment for cancer patients in Hungary. It shows potent anticancer activity on cell lines by deeply interfering with glucose metabolism and affecting expressions of several kinases. In in vivo experimental models, Avemar is also effective by enhancing the activity of the immune system such as stimulating NK cell activity (by reducing MHC I molecule expression), enhancing TNF secretion of the macrophages, increasing ICAM 1 molecule expression on the vascular endothelial cells. All of these lead to apoptosis of tumor cells. The wide range of biological activity of Avemar probably cannot be explained by only one active ingredient. Since there are numerous experimental data and the clinical benefit repeatedly confirmed Avemar can be one of the most potent and best researched food supplements available for cancer patients.
... The conversion of DMBQ into its biologically more active forms requires β-glucosidase enzyme [3]. Wheat germ is fermented by Saccharomyces cerevisiae yeasts [4] or treated with Lactobacillus plantarum dy-1 [5]. Fermented wheat germ extract (FWGE) is available in both human (Avemar®) and veterinary (Immu-novet®) medicine. ...
... Fermented wheat germ extract (FWGE) is available in both human (Avemar®) and veterinary (Immu-novet®) medicine. These products are aqueous extractions, which are fermented by Saccharomyces cerevisiae, and they contain several biologically active molecules [4,6]. FWGE is applied as an adjuvant in human cancer therapy, because benzoquinones have antimetastatic [2], antimetabolic [6], antiangiogenic [7], and antiproliferative properties and are able to induce apoptosis [5,8]. ...
... FWGE is applied as an adjuvant in human cancer therapy, because benzoquinones have antimetastatic [2], antimetabolic [6], antiangiogenic [7], and antiproliferative properties and are able to induce apoptosis [5,8]. Furthermore, FWGE can enhance the cellular immune response [4,9] and has an antioxidant effect [2]. ...
The effect of fermented wheat germ extract (FWGE) (Immunovet®) was evaluated with cotreatments with deoxynivalenol (DON) and T-2 toxin (T-2). These mycotoxins are produced by Fusarium mold species. The effects of FWGE on IPEC-J2 with DON and T-2 have not been studied until now. The IPEC-J2 porcine, nontumorigenic cell line was selected to investigate the outcome of the individually and simultaneously added compounds, as it has in vivo-like properties. The cells were treated for 24 h with the selected solutions; then, the IPEC-J2 cells were allowed to regenerate in a culture medium for an additional 24 h. In our results, DON and T-2 significantly increased the adverse impacts on cell viability and integrity of the cell monolayer. To elucidate the extent of oxidative stress, extracellular H2O2 concentrations and intracellular reactive oxygen species (ROS) were measured. FWGE appeared to be beneficial to IPEC-J2 cells given the separately and significantly decreased ROS levels. 1% and 2% FWGE could significantly reduce mycotoxin-induced oxidative stress. In conclusion, the results demonstrate that FWGE exerted protective effects to counteract the oxidative stress-provoking properties of applied fusariotoxins in the nontumorigenic IPEC-J2 cell line.
... Clinically, the process of tumor cachexia leads to emaciation, weakness and fatigue with significant impact on quality of life [1]. On the cellular level, beside others tumor cachexia results in a suppression of the immunological response and metabolic dysfunction [3] . In addition, recent data have identified tumor cachexia as an independent predictor of shorter survival and suggest that cancer patients with significant body weight loss have an increased risk of treatment failure [2,3]. ...
... On the cellular level, beside others tumor cachexia results in a suppression of the immunological response and metabolic dysfunction [3] . In addition, recent data have identified tumor cachexia as an independent predictor of shorter survival and suggest that cancer patients with significant body weight loss have an increased risk of treatment failure [2,3]. These findings support the early therapeutic intervention like the use of specific nutriments even before the onset of significant body weight loss, particularly in cancers well known to induce severe cachexia like pancreatic cancer [3] . ...
... In addition, recent data have identified tumor cachexia as an independent predictor of shorter survival and suggest that cancer patients with significant body weight loss have an increased risk of treatment failure [2,3]. These findings support the early therapeutic intervention like the use of specific nutriments even before the onset of significant body weight loss, particularly in cancers well known to induce severe cachexia like pancreatic cancer [3] . One of the nutrition supplements for cancer patients in current clinical use is fermented wheat germ extract (FWGE) which is available as an over the counter dietary supplement in several parts of the world under the brand name Avemar ® . ...
Background
Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-α and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE.
Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies.
Conclusion
In conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.
... The exact chemical composition of FWGE, which is currently used as nutriment for cancer patients is not completely known [1]. It contains two quinones, 2methoxy benzoquinone and 2,6-dimethoxybenzquinone that likely play a significant role in exerting several of its biological properties [2]. ...
... It contains two quinones, 2methoxy benzoquinone and 2,6-dimethoxybenzquinone that likely play a significant role in exerting several of its biological properties [2]. Preclinical in vitro and in vivo data suggested antiproliferative, antimetastatic and immunological effects of FWGE [1][2][3][4][5][6][7]. In cell lines studies, FWGE induced programmed cell death via the caspase-PARP-pathway [7,8]. ...
... Several established anticancer drugs like fludarabine, cytarabine and gemcitabine exert at least in part their cytotoxic activity by inhibiting ribonucleotide reductase [11]. An inhibitory activity on ribonucleotide reductase could also be demonstrated for FWGE, allowing FWGE to interfere with nucleic acid-synthesis by several pathways [1,8,11]. ...
Fermented wheat germ extract (FWGE) is currently used as nutrition supplement for cancer patients. Limited recent data suggest antiproliferative, antimetastatic and immunological effects which were at least in part exerted by two quinones, 2-methoxy benzoquinone and 2,6-dimethoxybenzquinone as ingredients of FWGE. These activity data prompted us to further evaluate the in vitro antiproliferative activity of FWGE alone or in combination with the commonly used cytotoxic drugs 5-FU, oxaliplatin or irinotecan in a broad spectrum of human tumor cell lines. We used the sulforhodamine B assay to determine dose response relationships and IC50-values were calculated using the Hill equation. Drug interaction of simultaneous and sequential drug exposure was estimated using the model of Drewinko and potential clinical activity was assessed by the model of relative antitumor activity (RAA). Apoptosis was detected by DNA gel electrophoresis.
FWGE induced apoptosis and exerted significant antitumor activity in a broad spectrum of 32 human cancer cell lines. The highest activity was found in neuroblastoma cell lines with an average IC50 of 0.042 mg/ml. Furthermore, IC50-range was very narrow ranging from 0.3 mg/ml to 0.54 mg/ml in 8 colon cancer cell lines. At combination experiments in colon cancer cell lines when FWGE was simultaneously applied with either 5-FU, oxaliplatin or irinotecan we observed additive to synergistic drug interaction, particularly for 5-FU. At sequential drug exposure with 5-FU and FWGE the observed synergism was abolished.
Taken together, FWGE exerts significant antitumor activity in our tumor model. Simultaneous drug exposure with FWGE and 5-FU, oxaliplatin or irinotecan yielded in additive to synergistic drug interaction. However, sequential drug exposure of 5-FU and FWGE in colon cancer cell lines appeared to be schedule-dependent (5-FU may precede FWGE).
Further evaluation of FWGE as a candidate for clinical combination drug regimens appeared to be warranted.
... Fermented wheat germ extract (FWGE), or Avemar, is an over-the-counter nutritional supplement that has been utilized by cancer patients since the discovery of its anticancer properties [4]. There is a wealth of published data demonstrating the ability of FWGE to inhibit cancer cell growth in vitro in malignancies such as ovarian, hepatocellular, T cell leukemia and B cell lymphoma, melanoma, squamous cell oral cancer, breast cancer and colon cancer as a monotherapy or when combined with other agents [5][6][7][8][9][10][11][12]. Control of tumor growth has been demonstrated in animal models of melanoma, colon cancer, and lymphoma [4,10,12,13]. ...
... FWGE is likely comprised of hundreds if not thousands of compounds [9]. One other group has published mass spectroscopy data from FWGE, yielding active proteins such as serpin, peroxidases, and glutenins, among others [22]. ...
Non-small cell lung cancer (NSCLC) continues to be the leading cause of cancer-related deaths. Although advances have been made in the past decade to treat such tumors, most options induce multiple side effects, and many patients discontinue therapy due to toxicity. Thus, the need remains for non-toxic, effective NSCLC therapies, especially in an elderly patient population. Our lab has previously identified a protein fraction from the nutraceutical Avemar®—dubbed fermented wheat germ protein (FWGP)—with demonstrated efficacy in lymphoma models both in vitro and in vivo. Here, we show that FWGP also has anti-tumor activity in vitro and in vivo against lung cancer. In vitro cytotoxicity against multiple lung cancer cell lines yielded IC50 values comparable to those previously established with the parent product, Avemar. Further, significant A549 xenograft growth inhibition occurred in athymic nu/nu mice receiving FWGP in both pre-radiated and non-radiated models when compared to the untreated control. Encouragingly, mice treated with FWGP experienced no toxicities as detected by weight reduction or blood chemistry analysis. These data support the further study of FWGP as a potential non-toxic therapy for lung cancer and other oncologic indications.
... Its production process is patented and is derived from the extraction of wheat germ and fermentation by Saccharomyces cerevisiae, followed by separation of the fermentation liquid, drying, and then granulation. As with other nutraceuticals, FWGE contains various molecules, but recent studies assume that the two quinones, 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone, which are present in wheat germ as glucosides, are likely to be responsible for some of the biological properties of FWGE [8,9]. ...
... After duplicates were removed, 20 studies were identified as acceptable for full-text evaluation and their full texts were read. At the end of the selection process, 16 articles [13,18,19,[21][22][23][24][25][26][27][28][29][30][31][32][33] were included in qualitative analysis, while four [9,17,35,36] were excluded for not complying with inclusion criteria. ...
... Its production process is patented and is derived from the extraction of wheat germ and fermentation by Saccharomyces cerevisiae, followed by separation of the fermentation liquid, drying, and then granulation. As with other nutraceuticals, FWGE contains various molecules, but recent studies assume that the two quinones, 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone, which are present in wheat germ as glucosides, are likely to be responsible for some of the biological properties of FWGE [8,9]. ...
... After duplicates were removed, 20 studies were identified as acceptable for full-text evaluation and their full texts were read. At the end of the selection process, 16 articles [13,18,19,[21][22][23][24][25][26][27][28][29][30][31][32][33] were included in qualitative analysis, while four [9,17,35,36] were excluded for not complying with inclusion criteria. ...
Fermented wheat germ extract (FWGE; trade name AVEMAR) is a natural compound derived from industrial fermentation of wheat germ. Its potential anticancer properties has emerged from recent studies. The aim of this systematic review is to summarize the data available in the scientific literature concerning the in vitro activity of FWGE on malignant cells. A systematic review of English articles in electronic databases has been performed. The primary outcomes of the review regarded types of cancer cell lines subjected to the investigation and the main results concerning cell viability, proliferation, and apoptosis observed within the studies. Sixteen articles were included in the final qualitative analysis. Various types of cancer cells treated with FWGE have been analyzed, showing mainly cytotoxic effects, alteration of the cell cycle, antiproliferative effects, and induction of apoptosis. FWGE can be a promising drug component in cancer treatment; however, further in vitro and in vivo studies are necessary to prove its effectiveness and safety in humans.
... Extracts of wheat germ fermented by Saccharomyces cerevisiae showed anti-arthritic, anti-cancer and immunostimulatory effects and are now commercially supplied as over-the-counter medical nutriments under the brand name Avemar [8][9][10][11][12]. The manufacturing process of fermented wheat germ extract is standardized to 2,6-dimethoxy-1,4-benzoquinone (DMBQ) (0.4 mg/g on dry matter basis) [13]. DMBQ and methoxy-1,4-benzoquinone (MBQ) are oxidized forms of methoxyhydroquinones which are linked to oligosaccharides via a beta-1,6-glycosidic bond. ...
... Total phenolics (mg GAE/g) 15.77 ± 0.03 a 10.14 ± 0.07 b Total flavonoids (mg CE/g) 13.69 ± 0.13 a 7.02 ± 0.07 b DMBQ (mg/g) Not detected 0.065 ± 0.003 UWG: untreated wheat germ extract; CWG: citric acid-treated wheat germ extract. Values with different letters in one row are significantly different (p < 0.05). ...
Until recently, fermentation was the only processing used to improve the functionality of wheat germ. The release of 2,6-dimethoxy-1,4-benzoquinone (DMBQ) from hydroquinone glycosides during the fermentation process is considered a marker of quality control. Here, we treated wheat germ extract with citric acid (CWG) to release DMBQ and examined the anti-inflammatory activity of this extract using a lipopolysaccharide-activated macrophage model. Treatment of wheat germ with citric acid resulted in detectable release of DMBQ but reduced total phenolic and total flavonoid contents compared with untreated wheat germ extract (UWG). CWG inhibited secretion of the pro-inflammatory cytokines tumor necrosis factor-α, interleukin (IL)-6, and IL-12 and the synthesis of cyclooxygenase-2, while UWG only decreased IL-12 production. CWG and UWG induced high levels of anti-inflammatory IL-10 and heme oxygenase-1. CWG specifically inhibited phosphorylation of NF-κB p65 and p38 kinase at 15 min after LPS stimulation. Our study showed that citric acid treatment enhanced the anti-inflammatory activity of wheat germ extract.
... Immature wheat kernels were more effective against two colon cancer cell lines (HT-29 and Caco-2) and HeLa cervical cancer cells [32]. Wheat germ extract (Avemar) has been reported to be involved in the apoptosis of MCF-7 breast cancer, Jukrat acute lymphoid leukemia T cell, HL-60 promyelocytic leukemia, H9 human lymphoid cell, and gastric cancer cells [33,34]. Avemar also was able to reduce nucleic acid synthesis in the tumor cell by altering the glucose uptake of cancer cells [33]. ...
... Yet another study, tocotrienols in whole wheat decreased the risk of heart disease whereas β-sito sterol was associated with a decrease in cholesterol [34]. A study with ferulic acid, which is the major component in whole wheat, showed that ferulic acid converted into DHFA by microbiota in gut resulting an increase in Bacteroidetes and Firmicutes [54]. ...
Wheat (Triticum aestivum L.) is one of the most commonly cultivated and consumed cereals throughout the world. Though phytochemicals and antioxidants in the cereal grains have not been studied as in fruits and vegetables, given the role of wheat in our diet plate, it is a given of primary importance to understand the chemistry of our major food, wheat. The presence of diverse polyphenols and their action against leading cause of death, including heart diseases, cancer, obesity, and diabetes, widens the scope of wheat. Phytochemicals such as phenolic acids, alkylresorcinols, flavonoids, phytosterols, and carotenoids are present in whole wheat. The majority of phytochemicals are located in the wheat bran/germ fraction, and they are the leading contributors to the health promoting activities. However, the presence of anti-nutrients and binding of phenolic acids with protein may have adverse effect on health. This review mainly focuses on studies that have been carried out in the past decade to present, emphasizing the importance of whole wheat and whole wheat based products in preventing major diseases and disease conditions, potentials threats, current lacks, and future prospects.
... A fermented and well standardized extract of wheat germ (trade-name Avemar®) was extensively studied for treatment of cancer and autoimmune diseases [19][20][21]. Avemar® is made through fermentation of wheat germ with baker's yeast (Saccharomyces cerevisiae), which harbors β-glucosidase activity. The aglycone-type 2methoxy benzoquinone and 2,6-dimethoxybenzoquinone were recognized as the most important bioactive compounds of this preparation [13,21]. ...
... Avemar® is made through fermentation of wheat germ with baker's yeast (Saccharomyces cerevisiae), which harbors β-glucosidase activity. The aglycone-type 2methoxy benzoquinone and 2,6-dimethoxybenzoquinone were recognized as the most important bioactive compounds of this preparation [13,21]. The protocol for the manufacture of Avemar® includes the use of a water-soluble extract of wheat germ, the fermentation of this extract, and further concentration and drying. ...
In the last decade, several studies described the promising cytotoxic activity of fermented wheat germ towards cancer cell lines and during in vivo clinical trials. Recent data suggested that the antiproliferative, antimetastatic and immunological effects of this preparation are mainly attributed to quinones. This study aimed at exploiting the potential of sourdough lactic acid bacteria fermentation to release 2-methoxy benzoquinone, and 2,6-dimethoxybenzoquinone, which are naturally present in wheat germ as glycosylated and non-physiologically active form.
Preliminarily, forty strains of lactic acid bacteria, previously isolated from wheat germ, were in vitro screened based on beta-glucosidase activity. Lactobacillus plantarum LB1 and Lactobacillus rossiae LB5 were selected based on the highest enzyme activity and on technology features. These strains were used in combination to ferment wheat germ. Raw wheat germ, without bacterial inoculum, was subjected to the same incubation and used as the control. The sourdough fermented wheat germ was characterized based on microbiological, physico-chemical and biochemical features. During incubation, the release of the non-glycosylated and physiologically active 2-methoxy benzoquinone, and 2,6-dimethoxybenzoquinone was almost completed during 24 h. Compared to the control, the concentration of the above bioactive compounds increased almost 4 and 6-folds. Both raw wheat germ (control) and sourdough fermented wheat germ were ex vivo assayed for the anti-proliferative activity towards various cell lines of germ cell tumor, colon carcinoma and ovarian carcinoma. While no effect was found for the raw wheat germ, the sourdough fermented preparation markedly and variously affected the human tumor cell lines. The values of IC50 ranged from 0.105 +/- 0.005 to 0.556 +/- 0.071 mg/ml, with a median value of IC50 of 0.302 mg/ml.
These results are comparable to those found for other well-known pharmaceutical preparations, and may disclose the use of the sourdough fermented wheat germ as an ingredient, nutritional supplement and/or anticancer drug.
... Laxative effect -Crude bran fiber stimulated peristalsis more than the lesser amount of whole bran fiber residue, resulting in more defecations and feces than whole bran [60] Germ Antidiabetic -Due to the high level of polyunsaturated acids and vitamin E, wheat germ oil (WGO), it has been shown to aid in oxidative stress reduction [3] -Policosanol, one of its components, aided in the reduction of high blood sugar and total cholesterol levels Anticancer -The effects of lectin present in wheat germ revealed a dose-response relationship, with the largest effects resulting from the highest concentrations at the longest culture period [29,51] -Avemar, a nontoxic wheat germ extract, which was approved by Hungary as a special nutrient for cancer patients, was found to inhibit glucose metabolism and affects the expression of several kinases, resulting in potent anticancer activity in cell lines -Avemar was also effective in in vivo experimental models by improving immune system activity, such as stimulating natural killer (NK) cell activity (by lowering major histocompatibility complex class 1 (MHC I) molecule expression), enhancing macrophage tumor necrosis factor (TNF) production, and increasing CD54 molecule expression on vascular endothelial cells -As a result of all of these factors, the tumor cells undergo apoptosis Antimicrobial -Wheat germ extract includes 2,6-dimethoxy-1,4-benzoquinone (DMBQ), which is extremely inhibitory to Staphylococcus aureus and Bacillus cereus [28] Antiaging -After treatment with fermented wheat germ (FWG), the amount of total cholesterol, triglycerides, and glucose in the serum of aged mice was lower [64] -FWG consumption increased antioxidant activity and enhanced the levels of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, and total antioxidant capacity while lowering malondialdehyde levels (a marker of oxidative stress) in several organs like the liver, brain, intestine, and serum ...
Wheat is considered as the most important cereal grain globally. It has a vast economic importance as it is used in producing bread, pastries, and household flour and serving as food for livestock among other uses. Different biological activities of wheat were correlated with the presence of polyphenols due to their antioxidant activities and other preventative capabilities. Wheat can also be used as an antidiabetic, anti-inflammatory, anticancer, antimicrobial, and antiaging agent. Omics has established itself during the past 20 years as a crucial tool for comprehending the internal systems of various plant systems including wheat using LC–MS, GC–MS, and UV spectrophotometry as analytical techniques. The current review represents in depth search regarding wheat cultivation, botanical description, economic significance, quantitative phytochemical characterization, and biological importance. Additionally, a critical assessment of the cited omics research on wheat was conducted with an emphasis on the analytical instrument, methods of analysis and results interpretation.
... FWGE is a complex mixture of thousands of molecules. Most of them have not been chemically identified yet (Telekes et al., 2009). Avemar has a direct pro-apoptotic effect in lymphoma cells and boosts host immune effector mechanisms (Barisone et al., 2018). ...
Introduction:
In addition to standard highly active antiretroviral therapy protocols, complementary therapies using natural compounds are widely used by human immunodeficiency virus (HIV)-infected human patients. One such compound is the fermented wheat germ extract (FWGE), named Avemar.
Materials and methods:
In this study, we investigate the effects of Avemar in a feline-acquired immunodeficiency syndrome model. MBM lymphoid cells were acutely infected by the American feline immunodeficiency virus (FIV)-Petaluma (FIV-Pet) and the European FIV Pisa-M2 strains. FL-4 lymphoid cells, continuously producing FIV-Pet, served as a model for chronic infection. Crandell Rees feline kidney (CRFK) cells were infected by either FIV-Pet or feline adenovirus (FeAdV) as a model for transactivation and opportunistic viral infection. Cell cultures were treated pre- and post-infection with serial dilutions of spray-dried FWGE (Avemar pulvis, AP), a standardized active ingredient in commercial Avemar products. Residual FIV and FeAdV infectivity was quantified.
Results:
In a concentration-dependent manner, AP inhibited replication of FIV strains in MBM and CRFK cells by 3-5 log. Low AP concentration prevented FIV-Pet release from FL-4 cells. Higher concentrations destroyed virus-producing cells with cytopathic effects resembling apoptosis. AP strongly inhibited FeAdV production inside CRFK cells but not in HeLa cells. Adenovirus particles are then released via the disintegration of CRFK cells.
Discussion:
This report is the first to describe the antiviral effects of Avemar. Further studies are required to confirm its in vitro and in vivo effects and to investigate the potential for its use as a nutraceutical in FIV-infected felines or HIV-infected humans.
Conclusion:
Avemar, as a single nutraceutical, inhibits FIV replication and destroys retrovirus carrier cells. An important conclusion is that prolonged Avemar treatment might reduce the number of retrovirus-producing cells in the host.
... To the best of our knowledge, no study reported that the supplementation of WGO might be a promising strategy for managing or decreasing the side effects of chemotherapeutic drugs such as olmutinib and TAA. Wheat germ extract has been reported to have an influential role in enhancing the activity of the immune system, such as stimulating NK cell activity by reducing the expression of MHC I molecules; by stimulating TNF secretion of the macrophages; and by increasing ICAM 1 molecule expression on the vascular endothelial cells, which leads to the apoptosis of tumor cells as a consequence [47]. ...
Thioacetamide (TAA) intoxication produces a reproducible standard animal model of induced liver and kidney injuries where free radicals are produced by phase I oxidation reactions, which eventually leads to liver and kidney failure. Wheat germ oil (WGO) is a unique food supplement with concentrated nutrient efficiency and has remarkable antioxidant functions. Olmutinib, on the other hand, is a chemotherapy drug considered safe for kidneys and the liver. Therefore, in this study, WGO and olmutinib were investigated for their effect on TAA-induced liver and kidney damage. Inflammatory markers; interleukin-1 beta (IL-1β); IL-6; and the levels of enzymatic markers ALT (Alanine aminotransferase), AST (Aspartate aminotransferase), LDH (Lactate dehydrogenase), and CK (creatinine kinase) in serum for liver and kidney were analyzed and evaluated along with histopathological changes in the tissue. Thirty male mice 4-6 weeks of age were grouped into five groups of six animals: the control group (saline) and the other groups (Groups II to V), which were given thioacetamide for two weeks. In addition, Group II continued with TAA; Group III was given olmutinib (30 mg/kg), Group IV was given the wheat germ oil (WGO) (1400 mg/kg), and Group V was given (olmutinib (30 mg/kg) + WGO (1400 mg/kg)) for five days. The results suggested that olmutinib treatment potentiated TAA-induced liver and kidney injury. At the same time, WGO efficiently alleviated TAA and TAA-olmutinib toxicity in Groups IV and V. The histological studies also showed reduced damage with WGO in the animal model. Hence, it was concluded that WGO could significantly reduce liver and kidney damage caused by TAA and olmutinib in mice.
... Fermented wheat germ extract (FWGE) is produced through the fermentation of wheat germ by Saccharomyces cerevisiae, separation of the fermentation liquid, drying and granulation (13). Recent studies reported that two quinones, 2-methoxy benzoquinone and 2,6-dimethoxy benzoquinone, which are present in wheat germ as glucosides, are likely responsible for some of the biological properties of FWGE (13)(14)(15). FWGE, also known as Avemar™, has been evaluated In Vitro and shown to have an inhibitory action on many cancer cell lines (16). A couple of clinical studies have been conducted to test the effects of FWGE supplement on patients undergoing conventional chemotherapy for melanoma (17) and colorectal cancer (18). ...
Oral carcinoma is one of the most aggressive cancers, and despite the advances in the therapy, its mortality is still high. An attention in cancer treatment has focused on natural compounds due to their potential beneficial effects on human health. In this study, the effects of dietary supplement Fermented Wheat Germ Extract (FWGE) on oral tongue squamous cell carcinoma (OTSCC) cells were investigated In Vitro using three cell lines (HSC-3, SAS, SCC-25) with variable aggressiveness. The cell viability was significantly decreased by the treatment with high concentration of FWGE in every cell line. Regarding migration and invasion, HSC-3 and SCC-25 cells were most sensitive to FWGE since their movement was significantly reduced with 5 and 10 mg/ml FWGE, while SAS was inhibited only with 10 mg/ml FWGE. Chemotherapeutic compounds (cisplatin and 5-fluorouracil) significantly reduced all OTSCC cells viability. Importantly, combination of these drugs with 10 mg/ml FWGE significantly decreased the cell viability compared to the treatment with the chemotherapeutics or FWGE alone. Based on these In Vitro experiments, the use of FWGE seems to improve the anticancer effects on OTSCC cells. Further In Vivo and clinical studies should be conducted to verify the positive effects of FWGE for OTSCC patients.
... Fermented wheat germ extract has been reported to show cancer preventive and therapeutic effects 22,23 . Notably, fermented wheat germ extract is clinically used as a non-prescription medical nutriment for cancer patients. ...
2,6-Dimethoxy-1,4-benzoquinone (2,6-DMBQ) is the major bioactive compound found in fermented wheat germ extract. Although fermented wheat germ extract has been reported to show anti-proliferative and anti-metabolic effects in various cancers, the anticancer potential and molecular mechanisms exerted by 2,6-DMBQ have not been investigated in non-small cell lung cancer (NSCLC) cells. Here, we report that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibiting activation of AKT and p38 MAPK. 2,6-DMBQ significantly suppressed anchorage-dependent and independent cell growth. Additionally, 2,6-DMBQ induced G2 phase cell cycle arrest through inhibiting the expression and phosphorylation of cyclin B1 and CDC2, respectively. Furthermore, 2,6-DMBQ strongly suppressed NSCLC cell migration through induction of E-cadherin expression. To determine the molecular mechanism(s) exerted by 2,6-DMBQ upon NSCLC cell lines, various signaling kinases were screened; the results indicate that 2,6-DMBQ strongly inhibits the phosphorylation of AKT and p38 MAPK. Additionally, the growth kinetics of cells treated with an AKT or p38 MAPK inhibitor in combination with 2,6-DMBQ indicate that 2,6-DMBQ suppresses NSCLC cell growth and migration through inhibition of AKT and p38 MAPK. Taken together, our results suggest that 2,6-DMBQ is a potential anticancer reagent against NSCLC cells and could be useful for treating lung cancer patients.
... In addition, FWGE increases tumor necrosis factor α (TNFα) production by macrophages, leading to improved immune response towards tumor cells, inhibition of angiogenesis, and increased apoptosis of the target cells [2]. Furthermore, FWGE is also able to increase interleukin 1α (IL-1α), IL-2, IL-5, and IL-6 levels [3], which are considered to be among the main regulatory molecules of the inflammatory response. Beyond its immunomodulatory effects, FWGE can enhance oxidative stress in tumor cells, inducing cell destruction caused by the produced free radicals [4]. ...
Bioactive compounds such as benzoquinone derivates presented in fermented wheat germ extract (FWGE) have several positive effects on overall health status of humans and animals alike. Since available data regarding the antioxidant activity of FWGE are limited, the aim of our study was to investigate its effects on the cellular redox homeostasis applying primary hepatocyte cell cultures of rat origin. Cultures were challenged to lipopolysaccharide (LPS) treatment for 2 or 8 hours to trigger inflammatory response. Further, culture media were concomitantly supplemented with or without FWGE (Immunovet®, 0.1% and 1%). In order to monitor the metabolic activity of the cell cultures, CCK-8 test was applied, while reactive oxygen species (ROS) production was measured using Amplex Red method. Malondialdehyde concentration of culture media as a specific marker of lipid peroxidation and the activity of glutathione peroxidase in cell lysates were also determined to monitor the redox status of the cultures. Based on our findings, it can be concluded that FWGE did not show cytotoxic effects in any applied concentration in cell cultures. Furthermore, FWGE efficiently decreased cellular ROS production and lipid peroxidation rate in case of LPS-induced inflammatory response. However, without LPS treatment, higher concentration of FWGE increased the rate of both ROS and malondialdehyde synthesis. This observation may refer to the prooxidant activity of high dose FWGE, which is an important beneficial effect regarding tumor cells. However, in case of noninflamed hepatocytes, considering the results of glutathione peroxidase activity, the application of the product did not result in severe oxidative distress. In accordance with the abovementioned findings, FWGE as a redox modulator, applied in the appropriate concentration, can serve as a promising candidate in the supplementary therapy of patients suffering from various inflammatory diseases, decreasing the free radical generation, thus avoiding the occurrence of cytotoxic effects.
1. Introduction
Based on its various beneficial biological effects, fermented wheat germ extract (FWGE) is successfully used in human medicine, mainly in the supportive therapy of people suffering from cancer. Bioactive compounds—most importantly different benzoquinone derivates—found in FWGE provide significant anticancer effects by influencing several cellular molecular mechanisms [1]. The FWGE stimulates the immune response against tumor cells by decreasing the MHC-I expression in the cell membrane and rendering cancer cells more effectively be recognized by natural killer (NK) cells [1]. In addition, FWGE increases tumor necrosis factor α (TNFα) production by macrophages, leading to improved immune response towards tumor cells, inhibition of angiogenesis, and increased apoptosis of the target cells [2]. Furthermore, FWGE is also able to increase interleukin 1α (IL-1α), IL-2, IL-5, and IL-6 levels [3], which are considered to be among the main regulatory molecules of the inflammatory response. Beyond its immunomodulatory effects, FWGE can enhance oxidative stress in tumor cells, inducing cell destruction caused by the produced free radicals [4]. Moreover, it has the ability to affect the carbohydrate and nucleotide metabolism of cancer cells. As an example, by the inhibition of hexokinase enzyme, it is able to decrease cellular ATP production and hinder the synthesis of pentoses, which are necessary for cell division [5]. Besides, FWGE impedes the activity of ribonucleotide reductase enzyme, directly decelerating the production of nucleotides needed for the DNA synthesis [6]. As a result of all the mentioned effects, FWGE is able to effectively decrease the proliferation of several malignant tumor types and to increase the apoptosis of these cells. These findings were initially confirmed in studies on HT-29 colorectal adenocarcinoma and HL-60 leukaemia cell lines [2]. By virtue of the efficient antitumor activity of FWGE, slower tumor growth rate has been detected, resulting in longer life expectancy. The FWGE-triggered improvement of the general health condition and the successful prevention of cancer-associated cachexia can also contribute to the better prognosis [7]. The decreased velocity of tumor growth and metastasis formation was described in case of numerous forms of tumors, such as in melanoma, in neuroblastoma, and in different cervical, testicular, or thyroid cancer types [6].
With the modulation of cellular and humoral immune response, FWGE can serve as a considerable effector not just in point of its immunomodulatory activity towards the neoplastic cells but also as a result of its general immunostimulatory effects [6]. Significant enhancement of the immune response was detected in FWGE treated, beforehand immunosuppressed mice, mainly resulting from the effective induction of differentiation and blast transformation of lymphocytes [8]. Beyond these results, FWGE is capable to be used in different immune-mediated diseases and to resolve the immunosuppressive effects caused by cyclophosphamide treatment [6, 9]. Considerable anti-inflammatory activity of FWGE was also detected based on the inhibition of cyclooxygenase (COX) enzymes, successfully supporting the action of nonsteroidal anti-inflammatory drugs (NSAIDs) [7].
Regarding the potential antioxidant effects of FWGE, containing high concentration of bioactive free radical scavenger molecules, only limited data are available. It was reported to decrease the amount of reactive oxygen species (ROS) such as superoxide anion radicals [10]. However, further research is required concerning the antioxidant activity of FWGE.
Following its application in human medicine, FWGE was also introduced to veterinary practice for companion animals, and based on its immunostimulatory, anti-inflammatory, and suggested antioxidant effects, it can serve as a proper candidate for maintaining and improving the general health status of the patients [11]. The application of FWGE can be of high importance in case of elderly, debilitated animals, suffering in various chronic diseases [12]. Furthermore, applying FWGE in companion animals affected by neoplastic diseases may also be promising, based on its antitumor activity and its ability to improve general health condition. In addition, FWGE can be also effectively used as a natural growth promoter in chicken [11] and turkey [12], contributing to improved productivity and health conditions of farm animals. In accordance with its antimicrobial activity, FWGE is proved to be efficient to treat mycoplasma infection [13] and to mitigate the spreading of Salmonella Typhimurium in chicken; further, the efficiency of different applied vaccines can be also enhanced by dint of FWGE’s immunostimulatory effects [14].
In spite of the above described effects—such as antitumor, immunostimulatory, anti-inflammatory, and antimicrobial activity—only limited data are available about the possible effects of FWGE on the antioxidant status of eukaryotic cells. Hence, in this present study, we aimed to investigate the effects of FWGE (Immunovet®) on the redox homeostasis as well as on the oxidative status of the liver. The investigations were carried out using primary hepatocyte cultures of rat origin, which model can be a proper tool to observe the exact molecular mechanisms on the cellular level. This in vitro study—applying rat as a widely used and accepted model animal in the research—can serve with relevant and valuable information about FWGE-induced alterations in farm and companion animals, moreover in humans.
2. Materials and Methods
All reagents used in the study were purchased from Sigma-Aldrich (Darmstadt, Germany), except when otherwise specified. Animal procedures described hereinafter were performed in strict accordance with the national and international law along with institutional guidelines and were confirmed by the Local Animal Welfare Committee of the University of Veterinary Medicine, Budapest, and by the Government Office of Pest County, Food Chain Safety, Plant Protection, and Soil Conservation Directorate, Budapest, Hungary.
2.1. Cell Isolation and Culturing Conditions
Isolation and culturing of primary rat hepatocytes were carried out based on our formerly developed and published method [15]. Briefly, hepatocyte isolation was performed using 8-week-old Wistar rats (approx. 200-250 g). Animals were kept and fed according to the actual Hungarian and European animal welfare laws. After carbon dioxide narcosis, median laparotomy was performed followed by the cannulation of the vena portae and the thoracic section of the vena cava caudalis. The liver was flushed and exsanguinated through the portal system, using different buffers and multistep perfusion. In order to recirculate the buffers, the effusing amount of the solutions was collected via the vena cava caudalis.
To perfuse the liver, 300 mL ethylene glycol tetraacetic acid (EGTA, 0.5 mM) containing Hanks’ Balanced Salt Solution (HBSS) buffer, 200 mL EGTA-free HBSS buffer, and finally, 130 mL EGTA-free HBSS buffer, supplemented with 50 mg type IV collagenase (Serva, Duisburg, Germany), and 2.5 mM CaCl2 and MgCl2 were used.
During the liver perfusion, all of the applied buffers were warmed up to 40°C and oxygenated with Carbogen (95% O2, 5% CO2); the velocity was set to 30 mL/min. The collagenase containing buffer was recirculated until the complete disintegration of the liver parenchyma. After excision of the liver and disruption of the capsule, cell suspension was filtered using sterile gauze sheets. Cell suspension was placed for 50 min into 25 mg/mL bovine serum albumin (BSA) containing ice-cold HBSS in order to avoid undesired cluster formation.
Hepatocytes were isolated using low speed multistep differential centrifugation (3 times, 100 × g, 2 min), and the gained pellets were resuspended in Williams’ Medium E supplemented with 50 mg/mL gentamycin, 2 mM glutamine, 20 IU/L insulin, 4 μg/L dexamethasone, 0.22% NaHCO3, and in the first 24 h of culturing with 5% foetal bovine serum (FBS).
After resuspendation, viability of hepatocytes was tested by trypan blue exclusion test, always exceeding 90%. The number of the cells was determined by cell counting in Bürker’s chamber to further adjust the appropriate cell concentrations to 10⁶ cells/mL. Hepatocytes were seeded onto 96- and 6-well Greiner Advanced TC cell culture dishes (Greiner Bio-One Hungary Kft., Mosonmagyaróvár, Hungary) previously coated with collagen type I (10 μg/cm2), using 200 μL/well seeding volume in the 96-well plates and 2 mL/well in the 6-well plates. Cultures were incubated at 37°C and 100% relative air humidity. Cell culture media were changed after 4 h, and confluent monolayer cell cultures were gained after 24 h incubation (Figure 1).
... Hidvegi, who first patented the water extract of fermented wheat germ, established MBQ and DMBQ as quality markers for its manufacture. Some studies have suggested that MBQ and DMBQ are the active compounds in fermented wheat germ extract, but other studies have shown that these benzoquinones do not affect its biological activities [6,10,11]. ...
Wheat germ is rich in quinones that exist as glycosides. In this study, we used Celluclast 1.5L to release the hydroxyquinones, which turn into benzoquinone, and prepared the water extract from enzyme-treated wheat germ (EWG). We investigated whether enzyme treatment altered the anti-inflammatory activity compared to the water extract of untreated wheat germ (UWG). UWG inhibited the production of inducible nitric oxide synthase (iNOS) and interleukin (IL)-12 and induced the production of IL-10 and heme oxygenase (HO)-1 in lipopolysaccharide (LPS)-stimulated macrophages. Enzyme treatment resulted in greater inhibition of iNOS and IL-10 and induction of HO-1 compared to UWG, possibly involving the modulation of nuclear factor (NF)-κB, activator protein 1 (AP-1) and nuclear factor erythroid 2-related factor (Nrf2). Mice fed UWG or EWG had decreased serum tumor necrosis factor (TNF)-α and increased serum IL-10 levels after intraperitoneal injection of LPS, with UWG being more effective for IL-10 and EWG more effective for TNF-α. Hepatic HO-1 gene was only expressed in mice fed EWG. We provide evidence that enzyme treatment is a useful biotechnology tool for extracting active compounds from wheat germ.
... In the present study, measuring of apoptosis using Acridine Orange-Ethidium Bromide Staining of tumor of FWGE treated mice, Fig (6c-d), showed induction of apoptosis in the marginal region,with the presence of some of healthy tumor cells in the core region of tumor. Telekes et al. [8] reported that, FWGE induces apoptosis in malignant hematologic and solid tumor cell lines and exhibits immunomodulatory activities. ...
Fermented wheat germ extract (FWGE) is a multi-substance composition and currently used as nutrition supplement for cancer patients. Nanotechnology holds promise for medication and nutrition because materials at the nanometer dimension exhibit novel properties different from those of both isolated atom and bulk material. Selenium nano particle (Nano-Se) is a novel Se species with novel biological activities and low toxicity. The aim of our study is to evaluate antitumor activity of fermented wheat germ extract and fermented wheat germ extract in combination with selenium nanoparticles (FWGE-nano-Se mixture). The two prepared materials were applied on an experimental carcinogenesis model in order to evaluate their in vitro and in vivo antitumor potential; against animal carcinogenesis "Ehrlich carcinoma". Cytotoicity assay of different concentrations of FWGE and FWGE-nano-Se mixture on EAC cells was evaluated by trypan blue exclusion method. In vivo studies were done by induction of solid tumors produced by intramuscular inoculation of EAC in the right thigh of the lower limb of each mouse and treating Erlich tumor bearing mice orally with FWGE and FWGE-nano-Se mixture for 6 weeks. Tumor volume was determined all over the experimental period. Blood, liver and tumor tissue samples were collected after 2 and 6 weeks from the beginning of treatment. The production of NO (X) , MDA,CAT,SOD,GSH , GPx, ALT,AST,GGT (as liver function test), urea, and creatinine (as kidney function test) were evaluated by colorimetric assays, also, histopathological examination of liver and tumor tissue and characterization of cell death within tumor tissue was evaluated. In vitro results showed treatment of EAC cells with different concentrations of FWGE (0.21-85 mg/ml) showed cytotoxicity with IC 50 at concentration of 0.8mg /ml , and in case of FWGE-nano-Se, showed cytotoxicity with IC 50 at concentration of 0.8 mg /ml FWGE +0.75 µg /ml nano-Se. Also, in vivo studies results of FWGE-nano-Se mixture treated group showed significant reduction in the tumor volume compared to positive control group and FWGE treated group. Moreover, results of antioxidant parameters showed significant increase in SOD, GSH, GPx and CAT and significant decrease NO (X) and MDA and improvement in liver and kidney function tests. Apoptosis and histopathological examination revealed that FWGE-nano-Se mixture has antimetastatic effect and induced apoptosis in Ehrlich carcinoma cells. We concluded that the anti-tumor mechanisms of FWGE-nano-Se may be mediated by preventing oxidative damage, improved liver and kidney function, decrease metastases of cancer cells and increae apoptosis. So FWGE-nano-Se might be a potential alternative agent for cancer therapy. Clinical trials will be needed to spur the development of FWGE-nano-Se as cancer therapeutic agents.
... The seriousness of these findings is, however, somehow lowered by the fact that they almost entirely originate in the laboratory of the founder of MGN 3. Independent studies usually employed their own extract [17]. Avemar is fermented wheat germ extract developed by Mate Hidvegi with documented anti-carcinogenic properties [18,19]. Some of the effects are mediated via inhibition of the glycolysis enzymes and apoptosis stimulation [20]. ...
... Certainly, a lot of healthy food has derived from wheat germ. A scientific study of 2009 published on Nutrition and Cancer has demonstrated special properties of Avemar, wheat germ extract, for cancer patients 8 . It shows potent anticancer activity on cell lines by interfering with glucose metabolism and changing expressions of several kinases. ...
... In the current study, two natural products, namely Avemar and Echinacea, were selected to investigate their possible role in supporting SC biology. Avemar is a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids that has been reported as safe and effective anticancer and immunomodulatory adjuvant therapy for human cancer [6]. Avemar also has a potential role to attenuate the cardiovascular symptoms induced by hypertension or diabetes. ...
Introduction
Activation of endogenous stem cell mobilization can contribute to myocardial regeneration after ischemic injury. This study aimed to evaluate the possible role of Avemar or Echinacea extracts in inducing mobilization and homing of CD34+ stem cells in relation to the inflammatory and hematopoietic cytokines in rats suffering from acute myocardial infarction (AMI).
Methods
AMI was developed by two consecutive subcutaneous injections of isoprenaline (85 mg/kg). AMI rats were either post-treated or pre- and post-treated daily with oral doses of Avemar (121 mg/kg) or Echinacea (130 mg/kg). In whole blood, the number of CD34+ cells was measured by flow cytometry and their homing to the myocardium was immunohistochemically assessed. Serum creatine kinase, vascular endothelial growth factor, interleukin-8 and granulocyte macrophage colony stimulating factor were determined on days 1, 7 and 14 after AMI. Sections of the myocardium were histopathologically assessed.
Results
Rats pre- and post-treated with Avemar or Echinacea exhibited substantial increases in the number of circulating CD34+ cells, peaking on the first day after AMI to approximately 13-fold and 15-fold, respectively, with a decline in their level on day 7 followed by a significant increase on day 14 compared to their corresponding AMI levels. Only post-treatment with Echinacea caused a time-dependent increase in circulating CD34+ cells on days 7 and 14. Such increases in circulating CD34+ cells were accompanied by increased homing to myocardial tissue 14 days after AMI. Interestingly, pre- and post-treatment with Avemar or Echinacea substantially increased serum creatine kinase on day 1, normalized its activity on day 7 and, on continued treatment, only Echinacea markedly increased its activity on day 14 compared to the corresponding AMI values. Moreover, both treatments modified differently the elevated serum vascular endothelial growth factor and the lowered granulocyte macrophage colony stimulating factor levels of the AMI group but did not affect the level of interleukin-8. These results were supported histopathologically by reduced inflammatory reactions and enhanced neovascularization.
Conclusion
Avemar and Echinacea extracts can effectively induce mobilization and homing of CD34+ stem cells to the myocardial tissue and thus may help in stem cell-based regeneration of the infarcted myocardium.
... In the present study, measuring of apoptosis using Acridine Orange-Ethidium Bromide Staining of tumor of FWGE treated mice, Fig (6c-d), showed induction of apoptosis in the marginal region,with the presence of some of healthy tumor cells in the core region of tumor. Telekes et al. [8] reported that, FWGE induces apoptosis in malignant hematologic and solid tumor cell lines and exhibits immunomodulatory activities. ...
Fermented wheat germ extract (FWGE) is a multi-substance composition and currently used as nutrition supplement for cancer patients. Nanotechnology holds promise for medication and nutrition because materials at the nanometer dimension exhibit novel properties different from those of both isolated atom and bulk material. Selenium nano particle (Nano-Se) is a novel Se species with novel biological activities and low toxicity. The aim of our study is to evaluate antitumor activity of fermented wheat germ extract and fermented wheat germ extract in combination with selenium nanoparticles (FWGE-nano-Se mixture). The two prepared materials were applied on an experimental carcinogenesis model in order to evaluate their in vitro and in vivo antitumor potential; against animal carcinogenesis "Ehrlich carcinoma". Cytotoicity assay of different concentrations of FWGE and FWGE-nano-Se mixture on EAC cells was evaluated by trypan blue exclusion method. In vivo studies were done by induction of solid tumors produced by intramuscular inoculation of EAC in the right thigh of the lower limb of each mouse and treating Erlich tumor bearing mice orally with FWGE and FWGE-nano-Se mixture for 6 weeks. Tumor volume was determined all over the experimental period. Blood, liver and tumor tissue samples were collected after 2 and 6 weeks from the beginning of treatment. The production of NO (X) , MDA,CAT,SOD,GSH , GPx, ALT,AST,GGT (as liver function test), urea, and creatinine (as kidney function test) were evaluated by colorimetric assays, also, histopathological examination of liver and tumor tissue and characterization of cell death within tumor tissue was evaluated. In vitro results showed treatment of EAC cells with different concentrations of FWGE (0.21-85 mg/ml) showed cytotoxicity with IC 50 at concentration of 0.8mg /ml , and in case of FWGE-nano-Se, showed cytotoxicity with IC 50 at concentration of 0.8 mg /ml FWGE +0.75 µg /ml nano-Se. Also, in vivo studies results of FWGE-nano-Se mixture treated group showed significant reduction in the tumor volume compared to positive control group and FWGE treated group. Moreover, results of antioxidant parameters showed significant increase in SOD, GSH, GPx and CAT and significant decrease NO (X) and MDA and improvement in liver and kidney function tests. Apoptosis and histopathological examination revealed that FWGE-nano-Se mixture has antimetastatic effect and induced apoptosis in Ehrlich carcinoma cells. We concluded that the anti-tumor mechanisms of FWGE-nano-Se may be mediated by preventing oxidative damage, improved liver and kidney function, decrease metastases of cancer cells and increae apoptosis. So FWGE-nano-Se might be a potential alternative agent for cancer therapy.
... It was reported that Avemar bolsters immunity by stimulating natural killer (NK) cell activity, enhancing tumor necrosis factor (TNF) secretion from macrophages, and increasing intercellular adhesion molecule 1 (ICAM-1) expression on vascular endothelial cells. These modulations in the immune profile aid in the apoptosis of cancer cells (7). Further, it was found that the beneficial effect of FWGE is mediated through interference with anaerobic glycolysis, the pentose cycle, and ribonucleotide reductase (8). ...
Introduction: Recent times have witnessed an unprecedented surge in phytochemical-based dietary supplements for the alleviation of various forms of cancer. Fermented wheat germ extract (tradename Avemar or MSC) has proven efficacy in this regard.
Materials and methods: To review the current status and future scope of fermented wheat germ extract, the PubMed and ScienceDirect databases have been explored.
Results: This product of high health repute is obtained by fermenting Triticum vulgaris grains with baker’s yeast, Saccharomyces cerevisiae. The bioactive ingredients responsible for the anticancer activity have been identified as 2,6-dimethoxy-p-benzoquinone and 2-methoxy benzoquinone. The progression of cancer is inhibited by immune modulation and antimetastasis.
Conclusions: This review focuses on the potential of Avemar as a supportive option to complement conventional cancer treatment, on the pitfalls encountered in this vision, and on the possibilities of widening the therapeutic spectrum.
... These data suggest that FWGE has the potential to provide benefits in cancer therapy [18,19]. 2-methoxy benzoquinone and 2,6-dimethoxybenzene, the two major components of FWGE, are suggested to exert main biological properties of FWGE [14,20]. Recent studies suggest that FWGE disrupts the anaerobic glycolysis and pentose cycle by targeting transketolase glucose-6-phosphate dehydrogenase, lactate dehydrogenase, and hexokinase [14,21,22], by which FWGE suppresses the allocation of precursors for DNA synthesis on tumor cells [13]. ...
Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death worldwide. Due to the difficulties of early diagnosis, curative treatments are not available for most patients. Palliative treatments such as chemotherapy are often associated with low response rate, strong adverse effects and limited clinical benefits for patients. The alternative approaches such as fermented wheat germ extract (FWGE) with anti-tumor efficacy may provide improvements in the clinical outcome of current therapy for HCC. This study aimed to clarify antitumor efficacy of FWGE and the combination drug effect of FWGE with chemotherapeutic agents, cisplatin and 5-fluorouracil (5-Fu) in human HCC cells, HepG2, Hep3B, and HepJ5. The present study indicated that FWGE exhibited potential to suppress HepG2, Hep3B, and HepJ5 cells, with the half maximal inhibitory concentrations (IC50) of FWGE were 0.494, 0.371 and 1.524 mg/mL, respectively. FWGE also induced Poly (Adenosine diphosphate ribose) polymerase (PARP) associated cell death in Hep3B cells. Moreover, the FWGE treatment further enhanced the cytotoxicity of cisplatin in all tested HCC cells, and cytotoxicity of 5-Fu in a synergistic manner in HepJ5 cells. Collectively, the results identified the anti-tumor efficacy of FWGE in HCC cells and suggested that FWGE can be used as a supplement to effectively improve the tumor suppression efficiency of cisplatin and 5-Fu in HCC cells.
Castration-resistant prostate cancer (CRPC) is a devastating and incurable disease. Combined therapy using conventional anticancer drugs and a proprietary medical nutriment, fermented wheat germ extract (FWGE), also known as Avemar, has been suggested as a treatment for progressing prostate cancer (PCa) patients, who have become resistant to first line hormonal therapy (gonadotropin releasing hormone, GnRH). The primary aim of this study was to test if this combined therapy would slow down disease progression in CRPC patients. We tested the nontoxic, readily available, inexpensive FWGE, together with the conventional treatment, GnRH analogue, in 36 CRPC patients. Although this is a pilot study, with the drawback of a statistically small sample size, some anticancer clinical activity of FWGE could be seen in the CRPC patients, as measured by prostate specific antigen doubling time (PSADT). We found that the intake of GnRH with FWGE for at least 4 months, improved the overall health as well as the quality of life (QOL) in 4 patients (11%) and was instrumental in extending the PSADT in about 17 (out of 26) patients (65.4%), six of whom were significant. Since no mentionable adverse events were noticed, this treatment may permit the postponement of chemotherapy for these patients.
Goldnanoparticles (AuNPs) have well applied in imaging and carriers of drugs and/or biomolecules for diseases
and cancers therapeutics, due to their tunable physicochemical properties, easy functionalized with biomole-
cules and biocompatibility. AuNPs conjugated with biopolymer such as collagen has been demonstrated that
increased the cell proliferation, migration and cell differentiation. Avemar (Ave) is a nutraceutical from natural
components and dietary supplement for healthcare of tumor related anorexia/cachexia. Moreover, Ave has re-
vealed the excellent bio-efficacy of anti-proliferation, cell cycle disturbing and apoptosis induction in numerous
types of tumor cells in in vivo and in vitro. However, the effects of Ave on cellular uptake mechanisms still
unclear. In this study, we fabricate the Ave-deposited AuNP-collagen nanocarrier (AuNP-Col-Ave) and in-
vestigate their endocytic mechanisms in transformed SCC oral cancer cells and non-transformed BAEC and HSF
cell lines. By using DLS assay, Ave-deposited AuNP-Col have shown a particle size of 303 ± 35.2 nm. Both
UV–vis absorption assay and FTIR spectrum analysis were also demonstrated that the Ave conjugated onto
AuNP-Col. Further, both MTT assay and Calcein AM assay were revealed that AuNP-Col-Ave induced a sig-
nificant cytotoxicity in cancerous SCC cells and showed nontoxicity and biocompatibility for non-transformed
BAEC and HFS cells. In addition, AuNP-Col-Ave has showed an excellent uptake capacity in all these cell lines as
compared to AuNP-Col group. Further uptake mechanisms analysis demonstrated that the macropinocytosis
seems to be the favorite endocytic mechanism during AuNP-Col-Ave internalized into these transformed and non-transformed cell lines. Altogether, this study is first validating the endocytic mechanisms of AuNP-Col-Ave
in transformed and non-transformed cell lines. Our findings will provide a novel insight for endocytic me-
chanisms of cellular uptake nutraceuticals during nutrition therapy and cancer prevention.
Non-Hodgkin lymphoma (NHL) affects over 400,000 people in the United States; its incidence increases with age. Treatment options are numerous and expanding, yet efficacy is often limited by toxicity, particularly in the elderly. Nearly 70% patients eventually die of the disease. Many patients explore less toxic alternative therapeutics proposed to boost anti-tumor immunity, despite a paucity of rigorous scientific data. Here we evaluate the lymphomacidal and immunomodulatory activities of a protein fraction isolated from fermented wheat germ. Fermented wheat germ extract was produced by fermenting wheat germ with Saccharomyces cerevisiae. A protein fraction was tested for lymphomacidal activity in vitro using NHL cell lines and in vivo using mouse xenografts. Mechanisms of action were explored in vitro by evaluating apoptosis and cell cycle and in vivo by immunophenotyping and measurement of NK cell activity. Potent lymphomacidal activity was observed in a panel of NHL cell lines and mice bearing NHL xenografts. This activity was not dependent on wheat germ agglutinin or benzoquinones. Fermented wheat germ proteins induced apoptosis in NHL cells, and augmented immune effector mechanisms, as measured by NK cell killing activity, degranulation and production of IFNγ. Fermented wheat germ extract can be easily produced and is efficacious in a human lymphoma xenograft model. The protein fraction is quantifiable and more potent, shows direct pro-apoptotic properties, and enhances immune-mediated tumor eradication. The results presented herein support the novel concept that proteins in fermented wheat germ have direct pro-apoptotic activity on lymphoma cells and augment host immune effector mechanisms.
The inhibitory effect of wheat germ water-soluble extract (GWWSE) on the proliferation activity, growth curve and cellular morphology of human breast cancer cell line MDA-MB231 in vitro was examined in this paper. The results showed that, the inhibition of defatted GWWSE on the proliferation of MDA-MB231 cell was remarkable and existed in dose-and time-dependent manners, which could be showed in the cell growth curve. With the increasing additive amount of GWWSE, the cancer cells decreased dramatically, even with negative increase. Through light microscope, after treated with GWWSE, MDA-MB231 cell showed an obvious decrease in quantity, with abnormal cell adherence and disappearing fiber-like cell, which was getting round and gathering into a cluster. The results above show that GWWSE has strong anti-breast cancer physiological activity in vitro and has the potential development prospect.
Both the medical practice and the scientific research proved that a number of nutritional products or nutritive elements could have a preventive role (especially in subjects in whom these reach a lower level than the physiological ones) in the prevention of cancer. The list of these products is quite large, but in this article we shall present only part of them. We emphasize that the aliments described are easy to find and are not expensive.
This study aimed to evaluate the anticarcinogenic activities of aqueous extract of fermented wheat germ with Lactobacillus plantarum dy-1 (LFWGE). The anticarcinogenic activities, including antiproliferative effects and the induction of apoptosis, were studied in human HT-29 colon cancer cells. The 2, 6-dimethoxybenzoquinone and total phenols contents in LFWGE were determined by HPLC and the Folin-Ciocalteu method. In addition, some functional proteins were separated and purified by gel filtration chromatography. Twenty-one proteins were identified by LC-MS-MS. The sugars isolated from LFWGE did not possess any anticarcinogenic activity. The results of an MTT assay showed high antiproliferative effects of LFWGE. In addition, LFWGE attenuated the progression from the G0-G1 to the G2-M phase of the cell cycle and LFWGE-induced cell apoptosis was associated with the activation of caspase-3. LFWGE and its major bioactive ingredients inhibited the proliferation of HT-29 cells via apoptosis and thus may be a potential anticarcinogenic agent.
An extract of fermented wheat germ (EFWG) was prepared by treatment with Aspergillus oryzae and in vitro antioxidant and cellular antioxidant capacities were measured. The induction of phase II detoxifying and antioxidant enzymes in exerting a cellular antioxidant capacity was determined. Treatment of wheat germ with A. oryzae significantly (p<0.001) increased the ferulic acid content, compared to controls, among 4 phenolic acids analyzed. The peroxyl radical-scavenging and reducing capacities and the cellular antioxidant capacity of EFWG were more potent than for extracts of wheat grain (EWG). The cellular antioxidant capacity of EFWG against AAPH and H2O2-induced oxidative stress was stronger than for EWG due to enhanced induction of the phase II enzymes HO-1, GST, and NQO-1. Potent in vitro and cellular antioxidant capacities of EFWG may result from an increased ferulic acid content due to treatment with A. oryzae.
Colorectal cancer is diagnosed in 1 million humans each year, and more than half a million people die from this disease annually, equivalent to approximately 8% of all cancer-related deaths in the world. Huge progress in the management of colorectal cancer has constantly been noted in various medical disciplines. Food appears to be a modifiable factor that has a critical role in colorectal carcinogenesis. Wheat is a well-known cereal grain that grows on arable land and is responsible for sustaining commercial food production worldwide. Wheat cereal is a rich source of dietary fiber. The latter is a major factor playing pivotal roles in regulation of normal function of gastrointestinal tract. Evidence of reduced colorectal cancer risk after intake of dietary fiber has shown heterogenous results. Recent clinical trials have shown that dietary fiber intake at the daily dose of 10. g probably has an inverse association with reduced colorectal cancer risk.
Nuruk, a traditional Korean fermentation starter, contains 2,6-dimethoxy-ρ-benzoquinoe (2,6-DMBQ), also found in fermented wheat germ extract, and has anti-cancer and immune supporting effects. The presence of 2,6-DMBQ was confirmed by high performance liquid chromatography and mass spectrometry. Among the five traditional nuruks tested, the highest 2,6-DMBQ content of 1.16±0.07 mg/50 g was obtained from nuruk purchased in Hwaseong. The results of this study may explain the health-promoting functions of traditional Korean alcoholic beverages that employ nuruk as a fermentation starter.
BACKGROUND: Fermented wheat germ extract (FWGE) is a multisubstance composition and, besides others, contains 2-methoxy benzoquinone and 2, 6-dimethoxy benzoquinone which are likely to exert some of its biological effects. FWGE interferes with anaerobic glycolysis, pentose cycle and ribonucleotide reductase. It has significant antiproliferative effects and kills tumor cells by the induction of apoptosis via the caspase-poly [ADP-ribose] polymerase-pathway. FWGE interacts synergistically with a variety of different anticancer drugs and exerted antimetastatic properties in mouse models. In addition, FWGE modulates immune response by downregulation of MHC-I complex and the induction of TNF-alpha and various interleukins. Data in the F-344 rat model provide evidence for a colon cancer preventing effect of FWGE.Clinical data from a randomized phase II trial in melanoma patients indicate a significant benefit for patients treated with dacarbazine in combination with FWGE in terms of progression free survival (PFS) and overall survival (OS). Similarly, data from studies in colorectal cancer suggested a benefit of FWGE treatment. Besides extension of OS and PFS, FWGE improved the quality of life in several studies. CONCLUSION: In conclusion, available data so far, justify the use of FWGE as a non-prescription medical nutriment for cancer patients. Further randomized, controlled and large scale clinical studies are mandatory, to further clarify the value of FWGE as a drug component of future chemotherapy regimens.
Background and aim
Anorexia/cachexia syndrome is frequently correlated with increased oxidative stress (OS). A fermented wheat-germ extract with a standardized benzoquinone content (brand name Avemar) has been shown to exert an intense antioxidant activity with no side effects. The aim of this study was to investigate the effects of Avemar in patients affected by head and neck cancer, correlating the variations with OS with the quality of life as assessed by the Spitzer’s index
Patients and methods
A cohort of 60 patients affected by head and neck tumours (stage IIIa, IIIb, IV) were enrolled in the study following an open-label protocol. The patients were assigned to two subgroups, A or B. Group A was treated with conventional oncological therapy alone, and group B was treated with Avemar in addition to standard therapy. After 2 months only 55 patients survived and could be evaluated (29 in the control group and 26 in the Avemar group). Each patient was checked for circulating concentrations of hydroperoxides using the FRAS III test
Results
The levels of OS significantly decreased after 2 months in the group receiving Avemar (group). The value of Spitzer’s index was significantly higher in group B, attesting to an improved quality of life
Conclusion
Although the specific active substance in Avemar has not yet been identified, the reduction in free oxygen radicals induced by it is correlated with a clinically significant improvement in the quality of life in patients with advanced cancer
Mass spectrometry is fast becoming an indispensable field for medical professionals. The mass spectrometric analysis of metabolites and proteins promises to revolutionize medical research and clinical diagnostics. As this technology rapidly enters the medical field, practicing professionals and students need to prepare to take full advantage of its capabilities. Medical Applications of Mass Spectrometryaddresses the key issues in the medical applications of mass spectrometry at the level appropriate for the intended readership. It will go a long way to help the utilization of mass spectrometry in medicine. * Provides a broad look at how the medical field is benefiting from advances in mass spectrometry. * Guides the reader from basic principles and methods to cutting edge applications. * There is NO comparable book on the market to fill this fast growing field.
Avemar, a product of industrial fermentation of wheat germ with a standardized content of benzoquinone and plant flavonoids, has been tested as an anti-cancer and immunomodulatory dietary supplement. Proposed mechanisms include anti-oxidant and anti-inflammatory actions. This study has determined whether these actions of Avemar may also be useful in the treatment of cardiovascular diseases. Two experimental rat models of cardiovascular remodeling were used in this project: the deoxycorticosterone acetate (DOCA)-salt-induced model of chronic hypertension (study I) and a high-carbohydrate/high-fat diet-induced model producing chronic symptoms of the metabolic syndrome and its associated cardiovascular complications (study II). Our results in these rat models of hypertension and diet-induced obesity show that treatment with Avemar improved cardiac function, decreased macrophage infiltration resulting in decreased collagen deposition in the ventricular myocardium, reversed an increased stiffness of the left ventricle in the diseased hearts and attenuated increased plasma malondialdehyde concentrations. In addition to the changes in the heart, Avemar reversed glucose intolerance, normalized systolic blood pressure and decreased visceral fat deposition in rats fed a high-fat/high-carbohydrate diet. In conclusion, the fermented wheat germ extract Avemar has a potential role in attenuating chronic hypertension, diabetes or metabolic syndrome-induced cardiovascular symptoms along with metabolic abnormalities such as glucose tolerance and obesity.
Avemar (MSC) is a nontoxic fermented wheat germ extract, which has been shown to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in sensitive and 5-FdUrd/Ara-C cross-resistant H9 human lymphoma cells. After 48 and 72 h of incubation, Avemar inhibited the growth of sensitive H9 cells with IC50 values of 290 and 200 microg/ml, whereas the growth of 5-FdUrd/Ara-C cross-resistant H9 cells was attenuated with IC50 values of 180 and 145 microg/ml, respectively. Treatment with 300 microg/ml MSC for 48 h caused dose-dependent induction of apoptosis in 48% of sensitive H9 cells. In cross-resistant H9 cells, incubation with 200 microg/ml Avemar for 48 h led to 41% of apoptotic tumor cells. Growth arrest of sensitive H9 cells after exposure to various concentrations of MSC occurred mainly in the S phase of the cell cycle, thereby increasing the cell population from 54 to 73% while depleting cells in the G0-G1 phase from 40 to 19%. Growth arrest in cross-resistant H9 cells occurred also mainly in the S phase, increasing the cell population from 45 to 68% while depleting cells in the G0-G1 phase from 45 to 31%. As MSC treatment likely overcomes 5-FdUrd/Ara-C resistance, further investigations to elucidate the exact mechanisms are warranted. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.
An orally applicable fermentation product of wheat germ containing 0.04% substituted benzoquinone (MSC) has been invented by Hungarian chemists under the trade name of AVEMAR. Oral administration (3 g/kg body weight) of MSC enhances blastic transformation of splenic lymphocytes in mice. The same treatment shortens the survival time of skin grafts in a co-isogenic mouse skin transplantation model, pointing to the immune-reconstructive effect of MSC. A highly significant antimetastatic effect of MSC has been observed in three metastasis models (3LL-HH, B16, HCR-25). The antimetastatic effect of MSC--besides the immune-reconstitution--may also be due to its cell adhesion inhibitory, cell proliferation inhibitory, apoptosis enhancing, and antioxidant characteristics, also observed in our in vitro experiments. It is even more noteworthy that combined treatment with MSC and one of the following antineoplastic agents (5-FU and DTIC)--both in wide use in every day clinical practice--exhibited a significantly enhanced antimetastatic effect in appropriate metastasis models (established from C38 mouse colon carcinoma and B16 mouse melanoma respectively) as compared to the effect elicited by any component of these therapeutic compositions (MSC + 5-FU and MSC + DTIC) administered alone. The results show that the fermented wheat germ extract (MSC) has more than an additive effect and synergistically enhanced the metastasis inhibitory effect of both antineoplastic agents studied till now. It is also worthy of mention that the synchronous treatment with MSC profoundly decreased the toxic side effects of the applied antineoplastic agents (decreased weight loss etc). Based on the biological effects of MSC--shown to be non-toxic by subacute toxicology studies--this product may be used as an adjuvant in the therapy of malignant neoplasia and other diseases caused by or following immune-deficiency.
The potential of oral treatment with AVEMAR (AVEMAR), a new benzoquinone-containing fermentation product of wheat germ, on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was studied. We assessed the effect of AVEMAR on the profile of autoantibody production and the response of Th1=Th2 related cytokines as well as the clinical picture of experimental SLE in the SLE-induced mice.
When the product was given in the pre-immunization period, down-regulation of autoantibody production (anti-dsDNA, mouse 16=6 Id, and anti-histones) following treatment with AVEMAR was noted (eg anti-dsDNA decreased from 0.898 0.097 OD at 405 nm to 0.519 0.103 OD following treatment). This effect was sustained for at least 4 weeks after discontinuation of the therapy. Serological manifestations associated with a delay in Th2 response (IL-4 and IL-10) were recorded (eg IL-4 decreased from 91.7 8.11 to 59.55 7.78 ng =ml in splenocyte condition media). The mice showed normal ESR, WBC and less than 100 mg/dl of protein in the urine in comparison to > 300 mg/dl protein in the SLE non-treated mice.
In conclusion, oral intake of AVEMAR can ameliorate the clinical manifestations of experimental SLE, via affecting the Th1=Th2 network inhibiting Th2 response.
The fermented wheat germ extract (code name: MSC, trade name: Avemar), with standardized benzoquinone content has been shown to inhibit tumor propagation and metastases formation in vivo. The aim of this study was to understand the molecular and cellular mechanisms of the anti-tumor effect of MSC. Therefore, we have designed in vitro model experiments using T and B tumor lymphocytic cell lines. Tyrosine phosphorylation of intracellular proteins and elevation of the intracellular Ca2+ concentration were examined using immunoblotting with anti-phosphotyrosine antibody and cytofluorimetry by means of Ca2+ sensitive fluorescence dyes, Fluo-3AM and FuraRed-AM, respectively. Apoptosis was measured with cytofluorimetry by staining the DNA with propidium iodide and detecting the cell population. The level of the cell surface MHC class I molecules was analysed with indirect immunofluorescence on cytofluorimeter using a monoclonal antibody to the non-polymorphic region of the human MHC class I. MSC stimulated tyrosine phosphorylation of intracellular proteins and the influx of extracellular Ca2+ resulted in elevation of intracellular Ca2+ concentration. Prominent apoptosis of 20-40% was detected upon 24 h of MSC treatment of the cell lines. As a result of the MSC treatment, the amount of the cell surface MHC class I proteins was downregulated by 70-85% compared to the non-stimulated control. MSC did not induce a similar degree of apoptosis in healthy peripheral blood mononuclear cells. Inhibition of the cellular tyrosine phosphatase activity or Ca2+ influx resulted in the opposite effect increasing or diminishing the Avemar induced apoptosis as well as the MHC class I downregulation, respectively. A benzoquinone component (2,6-dimethoxi-p-benzoquinone) in MSC induced similar apoptosis and downregulation of the MHC class I molecules in the tumor T and B cell lines to that of MSC. These results suggest that MSC acts on lymphoid tumor cells by reducing MHC class I expression and selectively promoting apoptosis of tumor cells on a tyrosine phosphorylation and Ca2+ influx dependent way. One of the components in MSC, 2,6-dimethoxi-p-benzoquinone was shown to be an important factor in MSC mediated cell response.
The fermented extract of wheat germ, trade name Avemar, is a complex mixture of biologically active molecules with potent anti-metastatic activities in various human malignancies. Here we report the effect of Avemar on Jurkat leukemia cell viability, proliferation, cell cycle distribution, apoptosis, and the activity of key glycolytic/pentose cycle enzymes that control carbon flow for nucleic acid synthesis. The cytotoxic IC(50) concentration of Avemar for Jurkat tumor cells is 0.2 mg/ml, and increasing doses of the crude powder inhibit Jurkat cell proliferation in a dose-dependent fashion. At concentrations higher than 0.2 mg/ml, Avemar inhibits cell growth by more than 50% (72 h of incubation), which is preceded by the appearance of a sub-G(1) peak on flow histograms at 48 h. Laser scanning cytometry of propidium iodide- and annexin V-stained cells indicated that the growth-inhibiting effect of Avemar was consistent with a strong induction of apoptosis. Inhibition by benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone of apoptosis but increased proteolysis of poly(ADP-ribose) indicate caspases mediate the cellular effects of Avemar. Activities of glucose-6-phosphate dehydrogenase and transketolase were inhibited in a dose-dependent fashion, which correlated with decreased (13)C incorporation and pentose cycle substrate flow into RNA ribose. This decrease in pentose cycle enzyme activities and carbon flow toward nucleic acid precursor synthesis provide the mechanistic understanding of the cell growth-controlling and apoptosis-inducing effects of fermented wheat germ. Avemar exhibits about a 50-fold higher IC(50) (10.02 mg/ml) for peripheral blood lymphocytes to induce a biological response, which provides the broad therapeutic window for this supplemental cancer treatment modality with no toxic effects.
MSC (Avemar) is a medical nutriment of which preclinical and observational clinical studies suggested an antimetastatic activity with no toxicity. This open-label cohort trial has compared anticancer treatments plus MSC (9 g once daily) vs anticancer treatments alone in colorectal patients, enrolled from three oncosurgical centres; cohort allocation was on the basis of patients' choice. Sixty-six colorectal cancer patients received MSC supplement for more than 6 months and 104 patients served as controls (anticancer therapies alone): no statistical difference was noted in the time from diagnosis to the last visit between the two groups. End-point analysis revealed that progression-related events were significantly less frequent in the MSC group (new recurrences: 3.0 vs 17.3%, P<0.01; new metastases: 7.6 vs 23.1%, P<0.01; deaths: 12.1 vs 31.7%, P<0.01). Survival analysis showed significant improvements in the MSC group regarding progression-free (P=0.0184) and overall survivals (P=0.0278) probabilities. Survival predictors in Cox's proportional hazards were UICC stage and MSC treatment. Continuous supplementation of anticancer therapies with MSC for more than 6 months is beneficial to patients with colorectal cancer in terms of overall and progression-free survival.
Avemar (Biromedicina Co., Budapest, Hungary), a wheat germ preparation with immunomodulant and antimetastatic activity, was applied simultaneously with cytostatic drugs of different modes of action, in vitro and in vivo, in order to find out whether this simultaneous administration exerts an antagonistic or a synergistic effect on the viability of cell cultures, tumor growth, and survival of animals, inoculated with a transplantable mouse tumor (3LL-HH). In vitro, Avemar did not influence the effect on the viability of MCF-7, HepG2, or Vero cells, exerted by Dacarbazine, 5-fluorouracyl, or Adriblastina. In vivo, Avemar, combined with Endoxan, Navelbine, and doxorubicin, did not prevent the tumor growth inhibitory effect of the cytostatic drugs. The combination of Avemar with the cytostatic drugs did not increase the toxicity of the cytostatic compounds, and did not exert any toxic effect. Avemar may be administered together with cytostatic drugs, without the risk of increasing toxicity or decreasing antiproliferative activity.
An open-label, matched-pair (by diagnosis, stage of disease, age, and gender) pilot clinical trial was conducted to test whether the combined administration of the medical nutriment MSC (Avemar) with cytotoxic drugs and the continued administration of MSC on its own help to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers compared with the same treatments without MSC.
Between December 1998 and May 2002, 22 patients (11 pairs) were enrolled in this study. At baseline, the staging of the tumors was the same in each pair (mostly pTNM = T2N0M0), with the exception of two cases in which patients in the MSC group had worse prognoses (metastasis at baseline). There were no significant differences in the average age of the patients, the length of treatment time (MSC) or follow-up, the number of patients with central venous catheters, the number of chemotherapy cycles, the frequency of preventive counterneutropenic interventions, or the type and dosage of antibiotic and antipyretic therapy used in the two groups.
During the treatment (follow-up) period, there was no progression of the malignant disease, whereas at end-point the number and frequency of febrile neutropenic events significantly differed between the two groups: 30 febrile neutropenic episodes (24.8%) in the MSC group versus 46 (43.4%) in the control group (Wilcoxon signed rank test, P < 0.05).
The continuous supplementation of anticancer therapies with the medical nutriment MSC helps to reduce the incidence of treatment-related febrile neutropenia in children with solid cancers.
Avemar, a fermented wheat germ extract, has been applied in the supplementary therapy of human cancers. Because tamoxifen is commonly used in the therapy of ER+ breast cancer, in this study the combined effect of tamoxifen and Avemar treatment was investigated on MCF-7 breast cancer cells, in order to detect a possible agonistic or antagonistic action. Cytotoxicity was measured by MTT assay, the percentage of mitoses and apoptotic cells was determined morphologically, apoptosis and S-phase was measured by flow cytometry, and estrogen-receptor activity was determined by semiquantitative measurement of the estrogen-responsive pS2 gene mRNA production. Tamoxifen (1 nM) alone had no effect on the percentage of the apoptotic cell fraction and significantly reduced the percentage of the S-phase, compared to untreated cells. Avemar (625 microg/mL) significantly increased apoptosis after 48 hours of treatment. Tamoxifen together with Avemar significantly increased apoptosis already 24 hours after starting treatment but had only a slight (not significant) effect on mitosis and S-phase. Estrogen-receptor activity of MCF-7 cells was enhanced by Avemar, decreased by tamoxifen, and was further decreased by combined tamoxifen and Avemar treatment. As apoptosis increased when Avemar was added to tamoxifen treatment, the use of supplementary therapy with Avemar in the case of ER+ breast tumors may enhance the therapeutic effects of tamoxifen.
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to have antitumor effects. Avemar has the potential to significantly improve the survival rate in patients suffering from malignant colon tumors. We studied its effects in the HT-29 human colon carcinoma cell line. Avemar had an inhibiting effect on colonies of HT-29 cells with an IC50 value of 118 microg/ml (7 days of incubation); this value could be decreased to 100 and 75 microg/ml in the presence of vitamin C. In the cell line examined, Avemar induced both necrosis and apoptosis, as demonstrated by Hoechst/propidium iodide staining. The incubation of cells with 3200 microg/ml Avemar for 24 hrs caused necrosis in 28% and the induction of apoptosis in 22% of the cells. Avemar inhibited the cell-cycle progression of HT-29 cells in the G1 phase of the cell cycle. In addition, Avemar inhibited the activity of the key enzyme of de novo DNA synthesis, ribonucleotide reductase. In addition, we determined the effects of Avemar on the activity of cyclooxygenase-1 and -2. Both enzymes were significantly inhibited by Avemar with IC50 values of 100 and 300 microg/ml, respectively. We outline new explanations for its antitumor activity, which might serve as the basis for further studies using Avemar.
To investigate the effect of the fermented wheat germ extract (Avemar)in patients with severe rheumatoid arthritis (RA).
Fifteen female RA (Steinbrocker II-III) patients, who had unsuccessfully tried two different DMARD treatments, were enrolled in an open-label, 1-year long, pilot clinical study. DMARD and steroid therapies were recorded and continued. All patients received Avemar as additional therapy. For measurement of efficacy the Ritchie Index, the Health Assessment Questionnaire (HAQ) and the assessment of morning stiffness were applied. Patients were evaluated at baseline, 6 and 12 months. For statistical analyses the Wilcoxon test was used.
At both 6 and 12 months, Ritchie index, HAQ and morning stiffness showed significant improvements compared with the baseline values. Dosages of steroids could be reduced in about half of the patients. No side effects of Avemar were observed.
Supplementation of standard therapies with a continuous administration of Avemar is beneficial for RA patients.
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Background: The positive effect of the wheat germ extract Avemar has already been proved in cancer. Compared to the control group significantly longer survival times were achieved in both in vivo experiments and clinical studies. Inhibition of cell growth was also detected in K562 human leukaemia cell line in vitro. Avemar given p.o.(3 g/kg) resulted in significant increase of the survival time compared to the control group (p<0.005 Mann-Whitney) in i.v. implanted K562 xenograft model, which was practically the same as the effect of Gleevec treatment. Since, the mechanism(s) of action of Avemar is still not properly characterized a kinase expression panel in K562 in vitro model was examined. Methods: K562 cells (8x10 ⁵ cell/ml), were treated with Avemar (500 μg/ml) and mRNS from 3–3 parallel samples and their appropriate controls were isolated 24, 48 hours after the treatment and 24 hours after washing the cells previously treated with Avemar for 48 hours. To determine the kinase expression pattern Kinase OpenArray™ plates were used, having over 500 kinase genes with controls in quadruplicates in each plate. Changes in expression was declared if the average value was over 1 (2-fold change in mRNA copy number) and the standard deviation was relatively small (2xSTDEV = AVERAGE). Results: We have found 16 kinases which expression has temporary or durative (maintained for 24 hour after washing) decreased (e.g.: CCL2, ABR, FLT1, EphB6, TGFa) and 30 which expression has increased (e.g.: CPT1B, IRE1, ITK, RON, LTK, EphB2, FASTK). Conclusions: Our result demonstrated that many of the kinases which expression was altered by Avemar treatment is known to participate in cell cycle, cell migration, apoptosis and signal transduction. Thus, our results might shed light on the main mechanism(s) of action of Avemar and raise the possibility to identify the active substance(es) of this natural extract.
No significant financial relationships to disclose.
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Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF 1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of Avemar with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by Avemar (50% inhibition). The combination of Avemar with Examestane increased the tumor growth inhibition to 60.4% compared to control. The other treatments did not exceed the effect of Avemar monotherapy. In xenograft model Avemar produced 50% tumor growth inhibition compared to control and was more effective than the other treatments Examestane (26%), Anastrasol (25%) or Tamoxifen (42%). Combined treatment with Avemar always improved efficacy within the range of 3–10%. Avemar showed similar efficacy when T47/D (49%) and MDA-MB-231 (52%) xenografts were compared. Conclusions: The tumor growth inhibitory effect of Avemar on ER positive MXT mouse breast carcinoma as well as in T47/D xenograft models are comparable (equal or better) to standard endocrine treatments. Avemar certainly did not reduce the effect of endocrine treatments. The antitumor activity of Avemar did not depend on the estrogen receptor status.
No significant financial relationships to disclose.
The fermented wheat germ extract (FWGE) nutraceutical (Avemar), manufactured under "good manufacturing practice" conditions and, fulfilling the self-affirmed "generally recognized as safe" status in the United States, has been approved as a "dietary food for special medical purposes for cancer patients" in Europe. In this paper, we report the adjuvant use of this nutraceutical in the treatment of high-risk skin melanoma patients.
In a randomized, pilot, phase II clinical trial, the efficacy of dacarbazine (DTIC)-based adjuvant chemotherapy on survival parameters of melanoma patients was compared to that of the same treatment supplemented with a 1-year long administration of FWGE.
At the end of an additional 7-year-long follow-up period, log-rank analyses (Kaplan-Meier estimates) showed significant differences in both progression-free (PFS) and overall survival (OS) in favor of the FWGE group. Mean PFS: 55.8 months (FWGE group) versus 29.9 months (control group), p = 0.0137. Mean OS: 66.2 months (FWGE group) versus 44.7 months (control group), p = 0.0298.
The inclusion of Avemar into the adjuvant protocols of high-risk skin melanoma patients is highly recommended.
The supposed immunostimulatory actions of MSC, a new fermented wheat germ extract standardized to its benzoquinone composition (trade name: AVEMAR) were studied examining blastic transformation of peripheral blood lymphocytes of mice treated with MSC. It was found that MSC significantly increased the degree of blastic transformation caused by Concanavalin A. Using the B10LP to C57Bl skin graft system, MSC (0.03 and 3.0 g kg(-1) applied orally) acted in favour of restoring the immune function. On the other hand, 2,6-dimethoxy-p-benzoquinone (DMBQ), applied in equivalent doses (0.012 and 1.2 mg kg(-l)), did not shorten the rejection time of skin grafts. The immune restoring effect, as well as the blastic transformation enhancing potential of MSC may be exploited in various cases of decreased immune response.
The fermented wheat germ extract with standardized benzoquinone composition has potent tumor propagation inhibitory properties. The authors show that this extract induces profound metabolic changes in cultured MIA pancreatic adenocarcinoma cells when the [1,2-13C2]glucose isotope is used as the single tracer with biologic gas chromatography-mass spectrometry. MIA cells treated with 0.1, 1, and 10 mg/mL wheat germ extract showed a dose-dependent decrease in cell glucose consumption. uptake of isotope into ribosomal RNA (2.4%, 9.4%, and 28.0%), and release of 13CO2. Conversely, direct glucose oxidation and ribose recycling in the pentose cycle showed a dose-dependent increase of 1.2%, 20.7%, and 93.4%. The newly synthesized fraction of cell palmitate and the 13C enrichment of acetyl units were also significantly increased with all doses of wheat germ extract. The fermented wheat germ extract controls tumor propagation primarily by regulating glucose carbon redistribution between cell proliferation-related and cell differentiation-related macromolecules. Wheat germ extract treatment is likely associated with the phosphorylation and transcriptional regulation of metabolic enzymes that are involved in glucose carbon redistribution between cell proliferation-related structural and functional macromolecules (RNA, DNA) and the direct oxidative degradation of glucose, which have devastating consequences for the proliferation and survival of pancreatic adenocarcinoma cells in culture.
It has been demonstrated for the first time that a wheat germ extract prevents colonic cancer in laboratory animals. Four-week-old inbred male F-344 rats were used in the study. Colon carcinogenesis has been induced by azoxymethane (AOM). Ten rats served as untreated controls (group 1). For the treatment of the animals in group 2, AOM was dissolved in physiologic saline and the animals were given three subcutaneous injections 1 week apart, 15 mg/kg body weight (b/w) each. In two additional groups Avemar (MSC), a fermented wheat germ extract standardized to 2,6-dimethoxy-p-benzoquinone was administered as a tentative chemo-preventive agent. MSC was dissolved in water and was given by gavage at a dose of 3 g/kg b/w once a day. In group 3, animals started to receive MSC 2 weeks prior to the first injection of AOM daily and continuously thereafter until they were killed 32 weeks later. In group 4 the basal diet and MSC were administered only. At the end of the experiment all the rats were killed by exsanguination, the abdominal large vessels were cut under a light ether anesthesia and a complete autopsy was performed. Percentage of animals developing colon tumors and number of tumors per animals: group 1 - 0 and 0; group 2- 83.0 and 2.3; group 3 - 44.8 (P < 0.001) and 1.3 (P < 0.004), group 4 - 0 and 0. All the tumors were of neoplastic nature also histologically. The numbers of the aberrant crypt foci (ACF) per area (cm(2)) in group 2 were 4.85 while in group 3 the ACF numbers were 2.03 only (P < 0.0001).
Metabolic profiling using stable-isotope tracer technology enables the measurement of substrate redistribution within major metabolic pathways in living cells. This technique has demonstrated that transformed human cells exhibit profound metabolic shifts and that some anti-cancer drugs produce their effects by forcing the reversion of these metabolic changes. By revealing tumor-specific metabolic shifts in tumor cells, metabolic profiling enables drug developers to identify the metabolic steps that control cell proliferation, thus aiding the identification of new anti-cancer targets and screening of lead compounds for anti-proliferative metabolic effects.
Avemar, the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, Avemar can inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of Avemar treatment have been shown in various human cancers, in cultures of in vitro grown cancer cells, in the prevention of chemical carcinogenesis, and also in some autoimmune conditions. This document reviews the clinical and experimental results obtained with this extract so far. Special references are made for its safety, including its coadministration with anticancer drugs, as well as for its immunomodulatory activity, its molecular targets, and its use in cancer clinical trials.
Macrophages activated by lipopolysaccharide and/or phorbol esters exhibited high sensitivity to Avemar, a fermented wheat germ extract. Avemar synergized with lipopolysaccharide and PMA in the induction of the transcription of cytokine genes and release of inflammatory cytokines. At higher concentrations the preparation had a significant negative effect on the proliferation and survival of activated myeloid cell types. Avemar treatment induced the synthesis of ICAM-1 and synergized with the ICAM-inducing effect of TNF, but had no effect on VCAM-1 expression on microvascular endothelial cells. The effect of Avemar on signaling pathways, which are involved in cell activation was studied on HeLa cells as a model system. Avemar treatment increased the activity of stress kinases in a concentration-dependent way, resulting in the activation of AP-1 transcription factor. NF-kappa B-sensitive reporters were also activated by Avemar; in contrast, no effect of the preparation was observed on PKA-sensitive signaling pathways.
Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in human HL-60 promyelocytic leukemia cells. After 24, 48, and 72 h of incubation, Avemar inhibited the growth of HL-60 cells with IC50 values of 400, 190, and 160 microg/ml, respectively. Incubation with MSC caused dose-dependent induction of apoptosis in up to 85% of tumor cells. In addition, Avemar attenuated the progression from G2-M to G0-G1 phase of the cell cycle and was also found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of de novo DNA synthesis. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.
"Avemar pulvis" is a powder consisting of an aqueous extract of fermented wheat germ, with the drying aids maltodextrin and silicon dioxide, standardized to contain approximately 200 microg/g of the natural constituent 2,6-dimethoxy-p-benzoquinone. The results of toxicological and clinical studies of this product demonstrate its safety for its intended use as a dietary supplement ingredient in the United States. Avemar pulvis has been used in Hungary since 1998 and is approved in that country, as well as in the Czech Republic, Bulgaria, and Romania, as a "medical nutriment for cancer patients." Acute and subacute toxicity studies using rodents orally administered Avemar pulvis showed that dose levels (2000 to 3000 mg/kg body weight [bw]/day) exceeding the normal recommended oral dosage (8.5 g/day or 121 mg/kg bw/day for a 70-kg individual) by up to approximately 25-fold caused no adverse effects. The test substance showed no evidence of mutagenicity or genotoxicity in vitro or in vivo. Clinical studies using Avemar pulvis as a supplement to drug therapy in cancer patients at doses of 8.5 g/day not only showed no evidence of toxicity, but also showed a reduction in the side effects of chemotherapy. Overall, it was concluded that Avemar pulvis would not be expected to cause adverse effects under the conditions of its intended use as an ingredient in dietary supplements.
Anti-inflammatory efficacy of the fermented wheat germ extract (FWGE, Avemar) in the rat adjuvant arthritis (AA) model was examined. To Wistar rats with AA, different doses of FWGE and anti-inflammatory drugs (indomethacin, dexamethasone) as monotherapies were administered and FWGE and either diclofenac or dexamethasone were also given in combination. Besides plethysmographies of the paws, histological investigations of synovial tissues were also performed along with detection of CD4+ and CD8+ T lymphocytes. Gene expressions of COX-1 and 2 were determined by real-time polymerase chain reaction (PCR). FWGE monotherapy significantly inhibited the development of the secondary (immune-mediated) response in AA, and dexamethasone and indomethacin exerted inhibitory effects in a degree comparable to that of FWGE. Histological analysis of the affected joints confirmed the results. FWGE inhibited COX-1 and -2, while indomethacin enhanced COX-2 gene expressions. FWGE had an additive interaction with diclofenac. It is concluded that FWGE has significant anti-inflammatory efficacy confirmed by plethysmography, histology, and real-time PCR.
The mechanism and treatment of cachexia and anorexia related to cancer (in Hungarian)
- Telekes
Telekes A and Horváth Zs: The mechanism and treatment of cachexia and anorexia related to cancer (in Hungarian). Háziorvosi Továbbképzõ Szemle 5, 381–386, 2000.
Immunologic and biochemical effects of the fermented wheat germ extract Avemar Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells
- C Illmer
- S Madlener
- Z Horvath
- P Saiko
- A Losert
Illmer C, Madlener S, Horvath Z, Saiko P, Losert A, et al.: Immunologic and biochemical effects of the fermented wheat germ extract Avemar. Exp Biol Med 230, 144–149, 2005. 21. Saiko P, Ozsvar-Kozma M, Madlener S, Bernhaus A, Lackner A, et al.: Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells. Cancer Lett 250, 323–328, 2007.
Antimetastatic effect of Avemar in high-risk melanoma patients (Abstract). 18th UICC International Cancer Congress
- L V Demidov
- L V Manziuk
- G Y Kharkevitch
- E Artamonova
- N Pirogova
Demidov LV, Manziuk LV, Kharkevitch GY, Artamonova EV, and Pirogova
NA: Antimetastatic effect of Avemar in high-risk melanoma patients (Abstract ). 18th UICC International Cancer Congress. Oslo, Norway: 30 June–
5 July, 2002, p. 48, 2002.
The mechanism and treatment of cachexia and anorexia related to cancer (in Hungarian) Háziorvosi Továbbképzõ Szemle 5
- A Telekes
- Horváth Zs
Telekes A and Horváth Zs: The mechanism and treatment of cachexia and
anorexia related to cancer (in Hungarian). Háziorvosi Továbbképzõ Szemle
5, 381–386, 2000.