Anti-Aging

Fermented Wheat Germ Extract (FWGE ) in the Treatment of Cancer and Autoimmune Diseases

FWGE , the product of industrial fermentation of wheat germ, possesses unique cancer-fighting characteristics. Taken orally, FWGE can inhibit metastatic tumor dissemination and proliferation during and after chemotherapy, surgery, or radiation. Benefits of FWGE 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.

INTRODUCTION

Wheat germ, if left in flour, has an adverse effect on the functional properties of dough and therefore on breadmaking quality. Therefore, most germ is milled as part of mill feed, and a smaller portion is separated during the milling process. Separated wheat germ is traditionally included in healthy foods, is consumed as is, or serves as raw material for extracts rich in vitamin E. During the 1990s, a new, fermented wheat germ extract for human consumption was invented by Professor Máté Hidvégi in Hungary.1 The standardized manufacturing technology included the extraction of wheat germ, the fermentation of the extract, followed by separation of the fermentation liquid, microencapsulation, drying, and granulation. The resulting powder was named FWGE pulvis (or simply FWGE ), and the granulate is also known as FWGE . For a 70-kg weight adult, the single daily dosage of FWGE contains 8.5 g of FWGE pulvis plus flavoring ingredients, such as fructose and arome. After being dissolved in 150 ml of cold water, FWGE should be drunk preferably before a meal. The product has been approved as a dietary food for special medical purposes in cancer patients by the National Institute of Food Safety and Nutrition of Hungary. FWGE has been consumed by cancer patients for more than 6 years. Since its invention, a series of in vitro and in vivo studies and clinical trials have been carried out to determine whether FWGE could help cancer patients struggling with both the effects of their disease and the side effects of standard anticancer therapy (SAT).

Fermented Wheat Germ Extract (FWGE ) in the Treatment of Cancer and Autoimmune Diseases

 Subsequently, evidence of the efficacy of the fermented wheat germ extract in some autoimmune diseases has also been found. At this time, sufficient study of this compound has been done and enough data have emerged that some useful and valid conclusions can be made regarding the value of FWGE as a supportive tool in therapy. The benefits observed, mechanisms of action known, and study results are summarized in this review. (In the following text and references, the terms “fermented wheat germ extract,” “FWGE ,” and its code name “MSC” denote the same preparation.)

COMPOSITION

The original composition of wheat germ is substantially modified due to extraction followed by fermentation; therefore, FWGE cannot be replaced by wheat germ, germinated wheat, or any extract or derivative of these. Methoxy-substituted benzoquinones, present originally in the crude wheat germ as glycosides and liberated as aglycones by glycosidases during fermentation, are the indicator compounds for quantitative standardization.2 FWGE is also characterized by its specific high performance liquid chromatography fingerprint spectra. FWGE  is currently manufactured by Biromedicina in Hungary in a Good Manufacturing Practice (GMP)- certified pharmaceutical plant in the Kunfeherto-Kiskunhalas region.

SAFETY

Much evidence is available to demonstrate the safety of FWGE under the conditions of its intended use.3 FWGE has been investigated in numerous animal and human studies of its efficacy; in none of these studies has any indication of adverse effects been identified. 

FWGE has been sold in numerous countries for many years with no reports of adverse effects. Finally, FWGE has been subjected to acute toxicity studies in the rat and mouse, a subacute toxicity study in the rat, and subchronic toxicity studies in the rat and mouse in addition to genotoxicity, mutagenicity, and carcinogenicity screening tests, and it has been evaluated for hematologic effects in multi-year studies in human cancer patients. Based on the absence of adverse effects, the acute oral LD50 of FWGE in male and female mice and rats was >2,000 mg/kg, and the no-observable adverse effect level (NOAEL) of the extract in a subacute study with rats was determined to be the tested dose of 2,000 mg/kg/day. The NOAEL of FWGE in a subchronic study with mice and rats was determined also to be the tested dose of 3,000 mg/kg/day.The effect of long-term administration of FWGE on the hematologic status of carcinoma patients was examined in two hospital centers in Hungary. Hematologic data included white blood cell count, red blood cell count, hemoglobin level, hematocrit, platelet count, erythrocyte sedimentation rate, lymphocyte count, neutrophil granulocyte count, monocyte count, eosinophil granulocyte count, and prothrombin level. After 1, 3, and 5 years of FWGE treatment, all values remained within normal limits.

Vitamin C

In an early animal study, the effects of FWGE alone and FWGE plus vitamin C on tumor growth and metastasis in laboratory mice and rats were studied.4 Involved were an aggressive variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M), and a human colon carcinoma xenograft (HCR25) in immunosuppressed mice.

 Effects on metastases were studied both with the primary tumors intact and after their surgical removal. Vitamin C alone had a significant inhibitory effect on metastases in some of these tumor models but not in others. However, combined treatment with FWGE plus vitamin C administered simultaneously profoundly inhibited metastases in all tumor models. Interestingly, in some tumor models, treatment with FWGE alone had a greater inhibitory effect on metastasis formation than did FWGE plus vitamin C. It was therefore recommended that if vitamin C is being administered, FWGE should be consumed at least 2 hours before or after treatment with vitamin C-containing preparations.

Cytostatic Drugs

To determine whether FWGE beneficial effects might or might not compromise the efficacy of a variety of cytostatic drugs commonly used in cancer treatment, researchers tested FWGE alone and in combination with those drugs in malignant cell lines and in animals with cancer.5 In vitro, FWGE neither increased nor decreased the effect on viability of MCF-7, HepG2, or Vero cells resulting from treatment with dacarbazine (DTIC), 5-fluorouracil (5-FU), or doxorubicin. In mice with transplanted 3LL-HH tumors, the combination of FWGE with cyclophosphamide, vinorelbine, and doxorubicin did not lessen those drugs’ inhibition of tumor growth. 

FWGE produced no toxic effects in the mice, and its addition to the treatment regimen did not increase the toxicity of the drug treatment. Strong synergism in antimetastatic activities was seen with the combined use of FWGE and cytostatic drugs: DTIC plus FWGE  in B16 mouse melanoma, muscle/lung metastasis model and 5-FU plus FWGE in C38 mouse colorectal carcinoma, spleen/liver metastasis model resulted in statistically complete eradication of lung and liver metastases, respectively.6 These results make us confident that FWGE may be administered along with these conventional chemotherapy drugs with little risk of negatively affecting the cytostatic drugs’ efficacy, or increasing their undesirable side effects.

Cytokines 

FWGE may safely be administered together with the cytokine preparations used in clinical practice. The antineutropenic efficacy of the hematopoietic cytokines plus FWGE in combination is better than that of the cytokines alone.3

Tamoxifen 

Researchers at the National Institute of Chemical Safety in Budapest conducted an in vitro study of the effects of a tamoxifen plus FWGE combination administered to cultures of the MCF-7 (ER+) breast cell line as a preclinical model of human breast cancer.7

MCF-7 cells were treated with tamoxifen and/or FWGE for 24, 48, and 72 h. Cytotoxicity was measured by MTT assay; the percentages of mitosis and apoptosis were determined by hematoxylin and eosin staining and by immunochemistry, and estrogen receptor activation was studied by semiquantitative determination of the estrogen-responsive pS2 gene mRNA production. The percentage of apoptotic and proliferating cell fraction (S-phase) was determined by flow cytometry. Tamoxifen had no effect on the percentage of apoptotic cell fraction, while significantly reducing the ratio of S-phase cells. After an exposure time of 48 h, FWGE increased apoptosis significantly. Tamoxifen + FWGE increased apoptosis significantly after 24 h, with a negligible effect on mitosis and S phase. Estrogen receptor activity of MCF-7 cells treated for 24, 48, and 72 h was enhanced by FWGE and decreased by tamoxifen as well as by tamoxifen + FWGE . The increase in apoptosis by the combined use of tamoxifen + FWGE suggests that the addition of FWGE to tamoxifen may enhance the efficacy of tamoxifen in ER+ breast cancer. There is no contraindication to their combination in clinical practice.

FWGE AND IMMUNITY

Evidence of the immunomodulatory effects of FWGE was first obtained in a study on the effect of the compound on immune function in mice.8 Results in this study showed that FWGE significantly increased the degree of blastic transformation of peripheral blood T lymphocytes stimulated by concanavalin A. 

In other experiments, C57B1 mice were given skin transplants from the coisogenic mice strain B10LP, which normally could be expected to be tolerated for 16–25 days before rejection. Thymectomized control (untreated) mice rejected the transplants at a gender mean of 52 (male) or 41 (female) days. Thymectomized mice treated with FWGE rejected the grafts at a mean of 29 days (male) or 33 days (female). Control (untreated) mice not thymectomized rejected the transplants at a gender mean of 21 or 29 days. These results, with immune function of mice seriously immunocompromised by thymectomy restored to near that of nonthymectomized mice (untreated), demonstrate the very significant immune restorative effects of FWGE treatment in these animals.8 Interestingly, other experiments done as part of this group, aimed at determining whether FWGE immunostimulatory effects could be ascribed to one active molecule, 2,6-dimethoxy-p-benzoquinone, showed they could not, as this substance administered alone did not shorten graft rejection time. From a therapeutic point of view, the immunomodulatory and immunorestoring effects of FWGE may be exploited in various clinical manifestations of impaired immune response. The potential of FWGE treatment on features of experimental systemic lupus erythematosus (SLE) in naive mice, induced by idiotypic manipulation, was also studied.9 When the product was given in the preimmunization period, downregulation of autoantibody production (anti-dsDNA, mouse 16/6 Id, and antihistones) after treatment with FWGE was noted (e.g., anti-dsDNA decreased from 0.898 OD at 405 nm to 0.519 after treatment). 

This effect was sustained for at least 4 weeks after discontinuation of therapy. Serologic manifestations were associated with a delay in the Th2 (interleukin [IL]-4 and IL-10) response (e.g., IL-4 decreased from 92 to 60 ng/ml in splenocyte condition media). The mice showed normal erythrocyte sedimentation rate and WBC, and less than 100 mg/dl of protein in the urine in comparison to >300 mg/dl protein in the SLE nontreated mice. It was concluded that oral intake of FWGE could ameliorate the clinical manifestations of experimental SLE by affecting the Th1/Th2 network inhibiting the Th2 response. Based on these results, a double-blind clinical study with FWGE in lupus patients was recently initiated.10 In mice, FWGE proved effective in the restoration of hemopoiesis in bone marrow impairment induced by sublethal irradiation and/or cyclophosphamide therapy.11 Elevation of the platelet count started on postirradiation day 7, and the baseline level was achieved on day 21. At the same time, no substantial increase was detected in the WBC count. As regards cyclophosphamide therapy, restoration of thrombopoiesis as well as of erythropoiesis could be observed as a result of FWGE treatment. These results are in consonance with the 5-year long clinical observation that FWGE has no hematotoxic side effect. A decrease in febrile neutropenia episodes during intensive chemotherapy of FWGE -treated pediatric cancer may help confirm the clinical relevance of bone marrow protection assessed in the experimental setting.

MOLECULAR TARGETS OF FWGE Although the one (or more) molecule of fermented wheat germ extract responsible for the wide variety of biologic effects of this medical food has not yet been identified, molecular targets of FWGE , which could explain the effects, are (at least, partially) known. PARP Proliferation, differentiation, and cell death are under similar molecular control in all mammalian cells. Cancer cells develop severe defects in the regulation of homeostasis and cell proliferation, including resistance to apoptosis. FWGE inhibited the growth of leukemia cells in a dose-dependent manner. Laser scanning cytometry and gel electrophoresis with Western immunoblotting of stained cells indicated that the growth-inhibiting effect was consistent with a strong induction of apoptosis by activating the caspase-3–catalyzed cleavage of the poly(ADP-ribose) polymerase (PARP) enzyme.12 PARP is a key player in DNA repair. The activity of this enzyme is extremely high in cancer cells.13 Cleavage of PARP results in genomic instability, leading to DNA fragmentation and thus to apoptosis in tumor cells. As the activity of PARP is accelerated in cancer cells, these cells can be selectively sensitized by PARP inhibitors (such as FWGE ) to agents (such as 5-fluorouracil [FU] or DTIC), inducing base excisions or lesions in DNA. It has also been indicated that besides apoptosis induction, the mechanism through which FWGE mitigates metastasis involves decreasing cell motility. It was further demonstrated that although FWGE induced apoptosis in different leukemic human cells, it did not trigger programmed cell death in their healthy, resting counterpart, peripheral blood mononuclear cells.

MHC-I

FWGE treatment resulted in a decrease in the MHC class I (MHC-I) protein level on the surface of tumor cells, and hence it may expose them to natural killer (NK) cell activity.14 As inhibition of tyrosine phosphatase activity also resulted in elevated downregulation of MHC-I molecules, control of protein tyrosine phosphorylation in this process was indicated. Involvement of lymphocyte-specific signaling molecules, the nonreceptor tyrosine kinase p56lck, and the receptor tyrosine phosphatase CD45 in the FWGE -triggered cell response has been excluded. A way for tumors to survive in the host environment is to evade the defense control of the host by mimicking themselves as normal cells for the survey of the immune system. Natural killer cells, which play an important role in antitumor defense, recognize and are blocked by the expression of MHC-I molecules on their target cells.15 Consequently, tumor cells develop an effective camouflage by expressing high levels of MHC-I to avoid recognition by NK cells. This is a common characteristic of metastatic tumor cells to avoid NK surveillance.16 As FWGE reduces the MHC-I level on human tumor cells, it may sensitize them against NK killing, thus reducing their metastatic activity. ICAM-1 Endothelial cells of the vasculature of human solid tumors are known to have decreased expression of ICAM-1 compared to normal endothelial cell tissue, and this phenomenon can be considered a tumor-derived escape mechanism because the development of an efficient leukocyte infiltrate of the tumor is impaired.17

 It has been shown that FWGE upregulates the expression of intercellular adhesion molecule-1 (ICAM-1) on tumor-derived endothelial cells and also potentiates the similar effect of the primary anticancer cytokine, tumor necrosis factor-alpha (TNF-α).18 Pentose Phosphate Pathway FWGE regulates tumor cell proliferation also by altering the rate of glucose intake and the synthesis of nucleic acid ribose through the nonoxidative steps of the pentose phosphate pathway (PPP).19 This effect of FWGE is most efficiently present in the ribosomal RNA fraction of cancer cells. As ribose is a close metabolite of glucose and ribosomal RNA is essential for de novo enzyme protein synthesis and cell proliferation, it is evident that inhibiting the formation of ribose from glucose to build ribosomal structures is one of the important underlying mechanisms by which FWGE regulates tumor cell growth. FWGE also has remarkable effects on lipid synthesis and the oxidation of the first carbon of glucose through the oxidative steps of the PPP. FWGE increases glucose oxidation in the PPP in a dose-dependent fashion and therefore acts as an important agent in controlling oxidative stress and damage to the cells. The oxidative steps of the PPP play a very limited role in the synthesis of ribose to build nucleic acids in tumor cells. Tumor cells broadly use nonoxidative reactions, whereas normal cells heavily depend on oxidative synthesis, and then recycling of ribose back to glycolysis through the nonoxidative steps. The selectivity of FWGE in inhibiting tumor cell proliferation but promoting normal immune cell expansion can be explained by its selective inhibitory action on unique metabolic steps only observed in cancer. 

The metabolic changes observed in FWGE -treated cancer cells provide explanations for the clinically detected weight gain and slow disease progression in FWGE -treated cancer patients. Increased PPP activity (glucose oxidation and pentose recycling) increases de novo fatty acid synthesis, chain elongation, and desaturation. It is also likely tThis effect of redistributing glucose carbon use from nonoxidative nucleic acid ribose synthesis to direct glucose oxidation and lipid synthesis is a novel mechanism of antiproliferative action only described in connection with FWGE treatment.20 FWGE treatment is likely associated with the phosphorylation or transcriptional regulation of metabolic enzymes that are involved in reverting glucose carbons from cell proliferation-related structural and functional macromolecules (RNA, DNA) to direct oxidative degradation of glucose. t decreased oxidative ribose synthesis is unable to supply tumor cells’ metabolic needs for reducing equivalents that would intensively be used for the reduction of ribonucleotides to deoxyribonucleotides during DNA replication. The simultaneous decrease in nucleic acid synthesis from glucose leads to a decrease in cell proliferation, which explains the slow disease progression and the increased survival rate of the patients. Decreased glucose consumption of the tumors also leads to a metabolic harmony with the host and weight gain in patients with even advanced cancers. As a result, FWGE -treated patients also have improved tolerance for surgeries, chemotherapy, or radiation therapy. 

It was demonstrated that FWGE treatment was about 50 times less effective in peripheral blood lymphocytes in inducing the aforementioned effects than in cancer (leukemia) cells, which provides a comfortable therapeutic window for FWGE to apply in patients as a supplemental treatment modality with minimal or no toxic side effects.12

Ribonucleotide Reductase

Ribonucleotide reductase (RR) is responsible for the conversion of ribonucleotides to deoxyribonucleoside triphosphates, which are precursors of DNA synthesis. Ribonucleotide reductase was demonstrated to be significantly upregulated in tumor cells in order to meet the increased need for dNTPs of these rapidly proliferating cells for DNA synthesis.21 The enzyme was therefore indicated as being an excellent target for cancer chemotherapy, and various inhibitors of RR have entered clinical practice or are under preclinical or clinical development. The enzyme consists of two subunits, the effector binding and the nonheme iron subunits. The inhibition of the nonheme iron subunit can be caused, for instance, by iron chelation or the free radical scavenging of a free tyrosine radical, which is needed for iron stabilization. To determine whether FWGE action in HT-29 human colon carcinoma cell line involves such RR inhibition, first an in situ enzyme assay was employed. Radiolabeled cytidine had to be reduced by RR in order to be incorporated into DNA. The in situ RR activity of HT-29 cells were inhibited by FWGE in a concentration-dependent manner. 

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