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Application of soy in cancer patients to reduce cachexia and increase apoptosis by fermental soy - A prospective pilot study
Abstract
Clinically, cachexia manifests with excessive weight loss in the setting of ongoing disease, usually accompanied by muscle wasting. It affects more than 5 million persons in the United States alone: Aids, cancer, rheumatoid arthritis. Other causes of weight loss include anorexia, sarcopenia, and dehydration. The major cause described in the scientific literature appears to be cytokine excess, particularly increase of IL-6 and TNF-α. Both nutritional support and anorexigenic agents play a role in the management of cachexia. A fermented soy product available in Germany and Austria, which was marketed in the US in 1987 for reduction of symptoms accompanied in cancer patients, was investigated. It was shown in a small-scale prospective study in prostate, mammary and ovarian cancer patients that a fermented soy product could reduce depression, stress and cachexia which were unresponsive to conventional therapy. Significant increase of body weight was achieved. Apoptosis markers in disseminated tumor cells like BAX/Bcl2-ratio, cell cycle inhibitor p21 and anti-proliferation factor Estrogen Receptor beta (ER-β) gene expressions were increased in prostate cancer and ovarian cancer patients. Breast cancer patients did show increased cell cycle inhibitor p21, however no increase in apoptosis or ER-β-expression. Results may confirm our assumption that cachexia and reduced apoptosis are linked via NFκB, at least for prostate and ovarian cancer patients. Results have to be confirmed in a larger clinical trial.
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Antihistamines or histamine H1-receptor antagonists are commonly used to treat a variety of allergic symptoms. Eosinophils are considered to play an essential role in the pathogenesis of allergy. Reduced eosinophil apoptosis is thought to be an important element in the formation of eosinophilia in allergic conditions such as allergic rhinitis, atopic eczema, and asthma. The aim of this study was to investigate the effects of two first-generation antihistamines diphenhydramine and chlorpheniramine on constitutive eosinophil apoptosis and on interleukin (IL)-5-afforded eosinophil survival. The role of c-Jun N-terminal kinase (JNK) in mediating the effects of antihistamines on eosinophil apoptosis was evaluated also. Apoptosis of isolated human eosinophils was assessed by measuring the relative DNA content of propidium iodide-stained cells and confirmed by morphological analysis. The activity of JNK was measured by Western blotting. Antihistamines were found to reverse the survival-prolonging effect of IL-5 in eosinophils by enhancing apoptosis. JNK was found to be activated slowly during diphenhydramine-induced eosinophil apoptosis. An inhibitor peptide specific for JNK, L-JNKI1 (JNK peptide inhibitor 1, L-stereoisomer), inhibited diphenhydramine-mediated eosinophil apoptosis. Our results suggest that first-generation antihistamines diphenhydramine and chlorpheniramine reverse IL-5-afforded eosinophil survival and that the enhanced apoptosis by antihistamines is mediated through activation of JNK. Thus, reversal of IL-5-afforded eosinophil survival may contribute to the antiallergic actions of diphenhydramine and chlorpheniramine.
Estradiol-17beta (E(2)) induces rodent hippocampal neural progenitor cell (NPC) proliferation in vitro, in vivo, and after brain injury. The purpose of the present investigation was to determine whether E(2)-induced proliferation observed in rodent model systems generalized to cells of human neural origin and the signaling pathway by which E(2) promotes mitosis of human NPCs (hNPCs). Results of these analyses indicate that E(2) induced a significant increase in hNPC proliferation in a time- and dose-dependent manner. E(2)-induced hNPC DNA replication was paralleled by elevated cell cycle protein expression and centrosome amplification, which was associated with augmentation of total cell number. To determine whether estrogen receptor (ER) and which ER subtype were required for E(2)-induced hNPC proliferation, ER expression was first determined by real-time RT-PCR, followed by Western blot analysis, and subsequently verified pharmacologically using ERalpha or beta-selective ligands. Results of these analyses indicated that ERbeta expression was predominant relative to ERalpha, which was barely detectable in hNPCs. Activation of ERbeta by the ERbeta-selective ligand, diarylpropionitrile, led to an increase in phosphorylated extracellular signal-regulated kinase, and subsequent centrosome amplification and hNPC proliferation, which were blocked by the MEKK antagonist, UO126, but not its inactive analog, UO124. These findings, for the first time, demonstrate the molecular cascade and related cell biology events involved in E(2)-induced hNPC proliferation in vitro. Therapeutic implications of these findings relevant to hormone therapy and prevention of neurodegenerative disease are discussed.
Interference with the innate apoptotic activity is a hallmark of neoplastic transformation and tumor formation. Modulation of the apoptotic cascade has been proposed as a new approach for the treatment of cancer. In this chapter, we discuss the role of apoptosis in ovarian cancer and the use of phenoxodiol as a model for the regulation of apoptosis and potential use as chemosensitizer for chemoresistant ovarian cancer cells.
The early detection of prostate cancer has resulted in an increase in the number of patients with localized prostate cancer and has paralleled the reported reduction in prostate cancer mortality. The increased rate of detection of patients with localized prostate cancer may also increase the risk of potentially morbid therapy in a patient with indolent cancer. Defining the biomarker correlates of prostate cancer virulence will facilitate the appropriate application and development of therapy for patients with early disease.
A 255 core prostate cancer tissue microarray (TMA) from 47 prostatectomy specimens with organ confined tumor was constructed. Prostate cancer foci of transition and peripheral zone origin were represented on the TMA. Further, replicate cores of the two Gleason grades comprising the Gleason score, representative of Gleason scores 5-9, were arrayed from each prostatectomy specimen. Standard immunohistochemical techniques were used to assess expression of nine, cell death and cell cycle regulatory proteins implicated in the pathogenesis of prostate cancer (bax, bcl-2, bcl-xL, bin1, CD95, mdm2, p21, p53, and NFkappaB).
The Spearman correlation coefficient revealed a strong correlation of bax, bin1, FAS, p65 and p21 expression with Gleason grade. Spearman correlation coefficients showed that expression of, bax and bin1, bax and MDM2, Bax and p21, and bax and p65 NFkappaB was highly associated. Other significant associations were identified between bin1 and p21, bin1 and MDM2, bin1 and p65 NFkappaB and between p21 and p65 NFkappaB. A model for predicting the biological potential of Gleason score 7 prostate cancer using multivariable logistic regression methods was developed. The findings also indicate that the profile of specific markers for Gleason grade 3 prostate cancer correlates with the overall context of the Gleason score.
These data support the view that important molecular differences exist among and between the Gleason scores. Furthermore, there is significant molecular heterogeneity among prostatectomy specimens containing Gleason grade 3 cancer. This observation may have broader implications regarding the determination of risk among patients with prostate cancer that is currently considered to be of either good prognosis or unclear prognosis, i.e. Gleason score 7 tumors.
To estimate the effect of independent practice association (IPA) model HMOs and the Kaiser Foundation Health Plan's group model on inpatient utilization of Medicare beneficiaries in the last 2 years of life, compared with traditional fee-for-service (FFS) coverage.
Data from the Centers for Medicare & Medicaid Services were linked to inpatient discharge data from the California Office of Statewide Health Planning and Development for 1991-2001. A sample of aged Medicare beneficiaries who died between January 1998 and June 2001 and were continuously enrolled during the 2 years before death in (1) FFS (n = 234,498), (2) an IPA (n = 109,577), or (3) Kaiser (n = 29,434) were selected.
The probability of at least 1 hospitalization, number of inpatient days given at least 1 hospitalization, and total inpatient days per year in the last 2 years of life were estimated for each subgroup. A 2-part regression model, which adjusted for age, sex, Medicaid status, race, ethnicity, and chronic condition associated with the last hospitalization, was applied to determine the HMO-FFS difference in inpatient utilization during the last 2 years of life.
During their last 2 years of life, decedents in IPAs and Kaiser used approximately 34% and 51% fewer inpatient days, respectively, than decedents in FFS.
Medicare beneficiaries who died while enrolled in an HMO, particularly Kaiser, had many fewer hospital days during the 2 years before death than beneficiaries who died with FFS coverage.
In a typical third-party payer situation--representative of most U.S. health care delivery--the payer is likely to have interests that are at odds with the patient and provider. The separation and overlap between Medicare and Medicaid for individuals eligible for both programs introduces an additional level of complexity: multiple masters over plans, providers, and patients. This creates opportunities for shifting costs and administrative burdens between states and the federal government, providers and governments, and patients and everyone else. Program designers who wish to minimize unwanted consequences must find ways to structure their programs to produce financial incentives that encourage the pursuit of societal goals, including appropriately shared intergovernmental responsibilities and appropriate plan, provider, and patient behavior. Here the authors review nine federal and state initiatives that use varying strategies to integrate Medicare and Medicaid services for vulnerable populations. For each initiative, the authors examine and critique program design features in three areas: (1) eligibility determination, (2) finance and administration, and (3) service delivery. They find a few strengths and many weaknesses in design. Future efforts would be well served by carefully considering the incentive structures designed into these initiatives and working to improve them in the next generation of Medicare-Medicaid integration efforts.
Regulation of the extracellular matrix turnover is a crucial process in wound healing and the progress of periodontal disease. It has been proposed that urokinase-type plasminogen activator (uPA), under the control of growth factors or cytokines, provides the proteolytic potential to the accomplishment of these cellular events. Epidermal growth factor (EGF) is one of the growth factors that has been shown to be active in uPA regulation.
In this study, we have assessed the effect of EGF on uPA expression in primary cultures of human gingival fibroblasts. We also studied the signaling pathways involved in this process and the role of the dietary phytoestrogens curcumin and genistein as potential modulators of this response.
Human gingival fibroblasts expressed a basal uPA activity, which was inhibited by genistein, but not by curcumin. After treatment with 10 ng/ml EGF, uPA production was strongly stimulated. Exposure to genistein and curcumin inhibited EGF-stimulated urokinase production, although only genistein showed a statistically significant inhibitory response. Using more specific inhibitors, we found that the mitogen-activated extracellular kinase and c-Jun N-terminal kinase (JNK) inhibitors PD98059 and SP600125 also blocked the EGF-dependent stimulatory effect. On the other hand, SB203580, inhibitor of the p38 member of mitogen-activated protein kinase family, did not alter this response. In accordance to these findings, EGF stimulated a potent activation of JNK and a mild activation of extracellular signal-regulated kinases 1/2. Finally, EGF stimulated the phosphorylation of its receptor and tyrphostin (AG1478), curcumin and genistein were able to inhibit this stimulatory effect.
These results indicate that EGF constitutes a strong stimuli on uPA expression in human gingival fibroblasts. Our data also shows that EGF-stimulated uPA production involves the activation of the extracellular signal-regulated kinases 1/2 and JNK signaling pathways and might be modulated by the natural phytoestrogens curcumin and genistein.
Dominant negative inhibition of nuclear factor kappa B (NF kappa B) signalling activity in a human osteosarcoma cell line (Saos2) results in malignant reversion and the induction of the osteoblast differentiating transcription factor, Runx2/Cbfa1. This observation suggests that there is an inverse relation between a transcription factor associated with malignant progression and chemoresistance (NF kappa B) and an osteoblast differentiating transcription factor (Runx2/Cbfa1).
To assess and correlate Runx2/Cbfa1 and NF kappa B (p65) immunoreactivity in human osteosarcoma.
Runx2/Cbfa1 and NFkappaB (p65) immunoreactivity was assessed on 11 paraffin wax embedded archival specimens of human primary osteosarcoma by standard immunohistochemical methods and scored on a scale of 0-3. A Pearson correlation analysis between Runx2/Cbfa1 and NF kappa B (p65) scores was established.
Runx2/Cbfa1 was expressed constitutively in all pathology specimens of human osteosarcoma. Of note, a chondroblastic osteosarcoma showed the highest Runx2/Cbfa1 immunoreactivity. A Pearson correlation did not support an inverse correlation between Runx2/Cbfa1 and NF kappa B (p65) scores (r = 0.57) in human osteosarcoma.
Runx2/Cbfa1 immunoreactivity does not inversely correlate with NF kappa B immunoreactivity, and thus cannot serve as an indirect measure of NF kappa B activity or an independent predictive or prognostic indicator.
Phenoxodiol, an isoflavone derivative of genistein with unknown mechanism of action, is currently being evaluated in early human cancer clinical trials. To determine the mechanism of antiproliferative effects of phenoxodiol, we examined its effects in a battery of human cell lines. Although we observed caspase-dependent apoptosis in HN12 cells as early as 24 hours after exposure, clonogenic death occurred only after 48-hour exposure despite caspase blockade by the general caspase inhibitor, benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (ZVAD)-fmk. Moreover, clear evidence of cell death as determined by nuclear morphology and plasmatic membrane damage occur despite ZVAD, suggesting that another mechanism besides caspase-dependent apoptosis is required for clonogenic death induced by phenoxodiol. In search for other potential antiproliferative effects, we assessed the effects of phenoxodiol in the cell cycle progression of human carcinoma cell lines. A significant G(1)-S arrest was observed by 12 hours of exposure in HN12 cell lines at concentrations > or =5 microg/mL. Cell cycle arrest occurred several hours (approximately 12 hours) before induction of apoptosis. Analysis of in vitro purified cyclin-dependent kinase (cdk) activity showed that phenoxodiol did not inhibit cdk activity. In contrast, cellular cdk2 activity obtained from HN12 cell lines exposed to phenoxodiol for 12 hours decreased by 60%, whereas cdk6 activity remained unaltered, suggesting that the loss of cdk2 activity was specific. Loss in cdk2 activity was preceded by the accumulation of the endogenous cdk inhibitor p21(WAF1). To assess the role of p21(WAF1) induction by phenoxodiol, we used HCT116 isogenic cell lines and showed that phenoxodiol induced G(1) arrest together with p21(WAF1) expression in wild-type clones. In contrast, p21(-/-) variants failed to show G(1) arrest. Finally, induction of p21 by phenoxodiol is p53 independent, as phenoxodiol induced p21 in HCT116 lacking p53. These data therefore indicate that phenoxodiol promotes G(1)-S arrest by the specific loss in cdk2 activity due to p53-independent p21(WAF1) induction. This novel feature of phenoxodiol may have clinical implications, as the majority of human malignancies have aberrations in cell cycle progression regulation.
Women with ovarian cancer who experience disease progression during or within 6 months of first-line treatment with platinum-based anticancer drugs are considered to have platinum-resistant tumors. These patients have an unfavorable prognosis, and they frequently seek complementary and alternative therapies (CAM). Historically, this represents an understudied and underreported component of ovarian cancer treatment.
This report describes the case of a woman with rapidly progressive, platinum-resistant ovarian cancer. Upon initiating self-directed treatment with Haelan951, a commercially available fermented soy beverage, she entered into a phase of prolonged disease stabilization including improvement in the serum tumor marker CA-125.
Fermented soy products are known to contain high concentrations of the isoflavone, genistein, and other compounds that exhibit anticancer activity in preclinical models. This case report supports the prospective evaluation of alternative therapies such as these in patients with platinum-refractory ovarian cancer.
To investigate the regulative effect of genistein on the apoptosis of the xenografted tumors of human ovarian carcinoma HO-8910PM cell on the nude mice.
Human ovarian carcinoma HO-8910PM were cultured in vitro. The models of xenografted tumor were established by the transplantation of human ovarian carcinoma HO-8910PM on nude mice. The nude mice were randomly divided into four groups of three treatment groups (in which genistein were administered ip at 5, 25 and 50 mg x kg(-1) x d(-1), respectively, for 4 weeks) and one control group, the cell cycle and apoptosis of the xenografted tumors were measured by flow cytometry, the expression of bcl-2, Fas and FasL gene of xenografted tumors were determined by the immunohistochemistry and the morphology of tumor cells was observed by electron microscope.
The tumor weights of 50 mg x xkg(-1) genistein group were more lighter (P < 0.05) compared to those of control group. The tumor cells in Go-G1 phase were increased, at saml time the cells in S-phase were decreased (P < 0.01) after the treatment of 50 mg x kg(-1) genistein. In addition the apoptosis rate of the cell treated with 50 mg x kg(-1) genistein group was (15.14 +/- 2.27)%, which was significantly higher than that in the control group (3.12 +/- 1.12)% (P < 0.01). The expression of bcl-2 of the xenografted tumors was decreased and the expression of Fas was increased in 50 mg x kg(-1) genistein group, both showing a significant difference from those in control group (P < 0.05). The apoptosis of the tumor cells were found more under electron microscopy in 50 mg x kg(-1) genistein group than those in control group.
Genistein could significantly inhibite the proliferation and induce the apoptosis of the HO-8910PM cell of xenografted tumors by regulating the cell cycle and apoptoic gene in the nude mice.
The role of ZAP-70 expression on the ex vivo response of blood cells from CLL and PLL patients to a combination of fludarabine, a purine analog, and genistein, a tyrosine kinase inhibitor was studied. Patient cells were studied for the expression of ZAP-70 mRNA and its relation to the induction of apoptosis in response to treatment with genistein 15-60 muM and/or fludarabine 3 muM. The combination of genistein and fludarabine resulted in a significantly increased induction of apoptosis relative to the fludarabine alone. The ex vivo patient cells with a high ZAP-70 expression underwent more apoptosis in response to genistein than did patient cells with a low ZAP-70 mRNA expression. In contrast, basal IL-10 mRNA expression correlated negatively with apoptosis induction in response to genistein (P < 0.01). These studies suggest that, in malignant B cells that express elevated levels of the ZAP-70 signaling molecule, genistein may inhibit the ZAP-70 tyrosine kinase activity, resulting in cell death. The ZAP-70 may serve as a target for therapy. In addition, these studies suggest that the IL-10 expression by malignant B cells may not only suppress anti-tumor T cell responses in vivo, but also promote the survival of malignant B cells despite treatment with chemotherapeutic agents.
Nuclear factor kappa B (NFkappaB) is a central participant in the metastasis and chemoresistance of colorectal cancer (CRC). However, it is not fully understood to what extent NFkappaB contributes to induction of the metastasis-associated matrix metalloprotease-9 (MMP-9) gene and sensitivity to the commonly used chemotherapeutic 5-fluorouracil (5-Fu) in CRC. Using the RKO human CRC cell line and two NFkappaB signaling deficient RKO mutants, we investigated NFkappaB's role in the induction of MMP-9 and 5-Fu sensitivity in RKO CRC cells. NFkappaB plays a predominant role in MMP-9 gene induction in RKO cells, as evidenced by the failure of tumor necrosis factor alpha (TNFalpha) to induce MMP-9 in either of the NFkappaB signaling mutants. RKO cells exhibit a robust, oscillatory NFkappaB activity in response to TNFalpha not seen in either of the NFkappaB mutant cell lines, which instead demonstrate diminished, nonoscillatory NFkappaB activation. Analysis of TNFalpha-induced phosphorylation and MMP-9 promoter recruitment of the p65 NFkappaB subunit revealed a significant reduction in p65 phosphorylation as well as reduced and altered recruitment of p65 to the MMP-9 gene promoter in the mutants compared to the parental RKO cell line. 5-Fu only activated NFkappaB in the parental RKO cells through induction of IkappaB-kinase (IKK) activity and increased sensitivity to 5-Fu is observed in both NFkappaB mutant lines. Our results suggest that TNFalpha-dependent induction of MMP-9 gene expression is tightly regulated by oscillatory/cumulative activation of NFkappaB and that 5-Fu stimulates NFkappaB and RKO CRC cell survival through induction of IKK activity.
Novel Th2 cytokine IL-25 has been shown to be elevated in allergic inflammation. We investigated the intracellular mechanisms regulating IL-25-induced Th2 cytokines and chemokines from human Th lymphocytes upon costimulation by anti-CD3 and anti-CD28 antibodies. Cytokines, chemokines, and phosphorylated p38 mitogen activated protein kinases (MAPK), c-Jun amino-terminal kinase (JNK) and extracellular signal-regulated protein kinase were analyzed by bead-based array using flow cytometry. Nuclear factor (NF)-kappaB and total MAPK were assessed by electrophoretic mobility shift assay and Western blot, respectively. IL-25 could synergistically induce the release of Th2 cytokines IL-4, IL-5 and IL-10, inflammatory cytokine IL-6, Th1 related chemokines CXCL9 and CXCL10, and chemokine CCL5 from anti-CD3 and anti-CD28 antibodies costimulated Th cells, especially memory Th cells. Costimulation could also upregulate the cell surface expression of IL-25 receptor on Th cells. Costimulation with or without IL-25 treatment could activate JNK, p38 MAPK and NF-kappaB. The upregulation of costimulation-induced IL-25 receptors and release of cytokines and chemokines from IL-25 treated costimulated Th cells were differentially regulated by intracellular JNK, p38 MAPK and NF-kappaB activity. Therefore, the optimal activation of Th cells by IL-25 for the release of Th2 cytokines and chemokines requires the CD3 and CD28 mediated costimulation of Th cells via the upregulation of IL-25 receptors and the activation of intracellular signaling pathways. This mechanistic study shows that IL-25 and CD28 costimulation can play pathophysiological roles by inducing inflammation and hyperresponsiveness through the production of both Th2 cytokines and chemokines from memory Th cells.
We evaluated (1) the prevalence of disseminated tumor cells (DTC) before and after first-line chemotherapy with carboplatin and paclitaxel in the bone marrow (BM) and peripheral blood (PB) of 57 patients with primary ovarian cancer and (2) the coexpression of the epithelial antigen EpCAM on DTC including the determination of apoptotic cells.
DTC were detected by immunocytochemistry applying the anti-cytokeratin (CK) antibody A45-B/B3. For double-labeling of DTCs, the antibodies M30 (apoptosis), HEA-125-FITC/Ber-EP4-FITC (EpCAM) were used.
Before chemotherapy, we identified DTC in 12/57 PB samples (21%) with a median number of 2 cells/20 ml (range 1-8) and in 25/46 BM samples (54%) with a median number of 5 cells/9x10E6 BM cells (range 1-28). Analysis of DTC in PB and BM before and after therapy was performed in 30 patients. In this subgroup, we identified DTC in 5/30 PB samples (16%) and in 15/30 BM samples (50%) before chemotherapy. After chemotherapy, DTC in PB were only detected in one patient but in the BM of 15/30 patients (50%). After chemotherapy, BM analysis revealed evidence that no DTC were detectable any longer in 9 patients, no significant change in DTC was documented in 14 patients and a significant enhancement of DTC was shown in 10 patients, including 8 patients who had no DTC before chemotherapy. DTC, still present after chemotherapy, co-expressed EpCAM and were non-apoptotic. In a univariable analysis, patients with a marked increase of DTC showed a significantly reduced PFS (p=0.041). A corresponding multivariable Cox regression analysis was not feasible due to the limited number of events. No correlation of DTC in BM and PB was found with patient's and tumor characteristics.
DTC were present in 50% of patients after first-line chemotherapy in ovarian cancer. It has to be considered whether patients with persisting EpCAM/CK-positive BM cells probably might benefit from an additive immunotherapy e.g. targeting EpCAM.
Natural products including plants, microorganisms and marine life provide rich resources for anticancer drug discovery. The root bark of Hibiscus syriacus has been used as an antipyretic, anthelmintic and antifungal agent in Asia. The antiproliferative effects of H. syriacus on human lung cancer cells were evaluated with bio-assays. The apoptotic activity was detected by Hoechst 33342 DNA staining and annexin V staining. The expression of caspases, p53, apoptosis induced factor (AIF), Bcl-2 and Bax were evaluated with Western blotting. The in vivo anticancer activity was evaluated using A549-xenograft model. The acetone extract of H. syriacus (HS-AE) exhibited a better cytotoxic effect on lung cancer cells than its methanol extract (HS-ME) or water extract (HS-WE). The IC(50) values of HS-AE on A549 (adenocarcinoma), H209 (squamous cell carcinoma) or H661 (large cell carcinoma) lung cancer cells ranged from 14 to 22 microg/ml after 48 hours of treatment. After 48 hours of exposure, HS-AE (15 microg/ml) induced A549 cell apoptosis to 48 +/- 3.6% of the control. Using Western blotting, HS-AE appears to suppress the expression of p53 and AIF. The results of the in vivo study showed that HS-AE suppresses growth in A549 subcutaneous xenograft tumors. These results indicate that HS-AE exerts significant and dose-dependent antiproliferative effects on cancer cells in vitro and in vivo, which prompts us to further evaluate and elucidate the bioactive component(s) of H. syriacus.