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PubMed | CAS Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Amitabha Medical Clinic and Healing Center, Shanghai JiaoTong University and Nanjing University
Type: Journal Article | Journal: Oncotarget | Year: 2015

The oncoprotein EZH2, as a histone H3K27 methyltransferase, is frequently overexpressed in various cancer types. However, the mechanisms underlying its role in urinary bladder cancer (UBC) cells have not yet fully understood. Herein, we reported that honokiol, a biologically active biphenolic compound isolated from the Magnolia officinalis inhibited human UBC cell proliferation, survival, cancer stemness, migration, and invasion, through downregulation of EZH2 expression level, along with the reductions of MMP9, CD44, Sox2 and the induction of tumor suppressor miR-143. Either EZH2 overexpression or miR-143 inhibition could partially reverse honokiol-induced cell growth arrest and impaired clonogenicity. Importantly, it was first revealed that EZH2 could directly bind to the transcriptional regulatory region of miR-143 and repress its expression. Furthermore, honokiol treatment on T24 tumor xenografts confirmed its anticancer effects in vivo, including suppression tumor growth and tumor stemness, accompanied by the dysregulation of EZH2 and miR-143 expressions. Our data suggest a promising therapeutic option to develop drugs targeting EZH2/miR-143 axis, such as honokiol, for bladder cancer treatment.


PubMed | Amitabha Medical Clinic and Healing Center and University of Kansas Medical Center
Type: Journal Article | Journal: Journal of clinical apheresis | Year: 2016

Plasma galectin-3 (Gal-3) is elevated in, and drives, diverse systemic inflammatory disorders, including cancer, cardiovascular diseases, and diabetes. Circulating Gal-3 promotes tumorigenesis and metastasis, as well as fibrotic remodeling, and is a promising therapeutic target. Apheresis has proven utility in reducing circulating disease-promoting substances, exemplified by the success of lipoprotein apheresis (LA) in abrogating cardiovascular disease progression in drug-refractory hypercholesterolemia patients. We compared the clinical utility of two FDA-approved LA systems in reducing plasma Gal-3 in humans.Plasma Gal-3 levels were assessed by ELISA in blinded samples drawn pre- and post-apheresis from hypercholesterolemia patients (n=10/group) undergoing therapeutic LA using either a heparin-induced extracorporeal LDL precipitation (HELP) or dextran sulfate-adsorption (DSA) system.Mean baseline plasma Gal-3 concentrations (SD) were 14.35.1 (range 6.6-22.8) and 14.52.8 (range 10.6-19.8) ng/mL in the HELP and DSA groups, respectively. Post-apheresis Gal-3 levels were respectively reduced by 19.4% and 22.7% in the HELP (P=0.0094) and DSA (P=0.0027) systems (paired t-tests); the difference between devices was insignificant (P=0.5288; Mann-Whitney). Post-treatment Gal-3 levels were 11.33.7 (HELP; range 4.5-16.3) and 11.33.8 (DSA; range 7.5-20.7) ng/mL.Circulating Gal-3 levels showed a statistically significant decrease in humans undergoing therapeutic LA. Although absolute Gal-3 reduction was 19-23%, this effect, combined with reducing atherogenic LDL and other inflammation mediators (e.g., CRP, fibrinogen, Lp-PLA2 ), may enhance apheresis clinical benefits. Applying new Gal-3-specific extraction technologies to apheresis may be advantageous in treating diverse pathologies that are promoted by elevated plasma Gal-3. J. Clin. Apheresis 31:388-392, 2016. 2015 Wiley Periodicals, Inc.


Cheng S.,Indiana University | Swanson K.,Indiana University | Eliaz I.,Amitabha Medical Clinic and Healing Center | McClintick J.N.,Indiana University | And 3 more authors.
PLoS ONE | Year: 2015

Pachymic acid (PA) is a purified triterpene extracted from medicinal fungus Poria cocos . In this paper, we investigated the anticancer effect of PA on human chemotherapy resistant pancreatic cancer. PA triggered apoptosis in gemcitabine-resistant pancreatic cancer cells PANC-1 and MIA PaCa-2. Comparative gene expression array analysis demonstrated that endoplasmic reticulum (ER) stress was induced by PA through activation of heat shock response and unfolded protein response related genes. Induced ER stress was confirmed by increasing expression of XBP-1s, ATF4, Hsp70, CHOP and phospho-eIF2α. Moreover, ER stress inhibitor tauroursodeoxycholic acid (TUDCA) blocked PA induced apoptosis. In addition, 25 mg kg-1 of PA significantly suppressed MIA PaCa-2 tumor growth in vivo without toxicity, which correlated with induction of apoptosis and expression of ER stress related proteins in tumor tissues. Taken together, growth inhibition and induction of apoptosis by PA in gemcitabine-resistant pancreatic cancer cells were associated with ER stress activation both in vitro and in vivo. PA may be potentially exploited for the use in treatment of chemotherapy resistant pancreatic cancer. © 2015 Cheng et al.


Jiang J.,Indiana University | Eliaz I.,Amitabha Medical Clinic and Healing Center | Sliva D.,Indiana University
International Journal of Oncology | Year: 2011

Since the use of dietary supplements as alternative treatments or adjuvant therapies in cancer treatment is growing, a scientific verification of their biological activity and the detailed mechanisms of their action are necessary for the acceptance of dietary supplements in conventional cancer treatments. In the present study we have evaluated the anti-cancer effects of dietary supplement ProstaCaid™ (PC) which contains mycelium from medicinal mushrooms (Ganoderma lucidum, Coriolus versi-color, Phellinus linteus), saw palmetto berry, pomegranate, pumpkin seed, green tea [40% epigallocatechin-3- gallate (EGCG)], Japanese knotweed (50% resveratrol), extracts of turmeric root (BCM-95®), grape skin, pygeum bark, sarsaparilla root, Scutellaria barbata, eleuthero root, Job's tears, astragalus root, skullcap, dandelion, coptis root, broccoli, and stinging nettle, with purified vitamin C, vitamin D3, selenium, quercetin, citrus bioflavonoid complex, β sitosterolzinc, lycopene, α lipoic acid, boron, berberine and 3.3′-diinodolymethane (DIM). We show that PC treatment resulted in the inhibition of cell proliferation of the highly invasive human hormone refractory (independent) PC-3 prostate cancer cells in a dose- and time-dependent manner with IC50 56.0, 45.6 and 39.0 μg/ml for 24, 48 and 72 h, respectively. DNA-microarray analysis demon-strated that PC inhibits proliferation through the modulation of expression of CCND1, CDK4, CDKN1A, E2F1, MAPK6 and PCNA genes. In addition, PC also suppresses metastatic behavior of PC-3 by the inhibition of cell adhesion, cell migration and cell invasion, which was associated with the down-regulation of expression of CAV1, IGF2, NR2F1, and PLAU genes and suppressed secretion of the urokinase plasminogen activator (uPA) from PC-3 cells. In conclusion, the dietary supplement PC is a promising natural complex with the potency to inhibit invasive human prostate cancer. Copyright © 2011 Spandidos Publications Ltd. All rights reserved.


Jiang J.,Indiana University | Thyagarajan-Sahu A.,Indiana University | Loganathan J.,Indiana University | Eliaz I.,Amitabha Medical Clinic and Healing Center | And 3 more authors.
Oncology Reports | Year: 2012

We have recently demonstrated that a natural dietary supplement BreastDefend (BD), which contains extracts from medicinal mushrooms (Coriolus versicolor, Ganoderma lucidum, Phellinus linteus), medicinal herbs (Scutellaria barbata, Astragalus membranaceus, Curcuma longa), and purified biologically active nutritional compounds (diindolylmethane and quercetin), inhibits proliferation and metastatic behavior of MDA-MB-231 invasive human breast cancer cells in vitro. In the present study, we evaluated whether BD suppresses growth and breast-to lung cancer metastasis in an orthotopic model of human breast cancer cells implanted in mice. Oral application of BD (100 mg/kg of body weight for 4 weeks) by intragastric gavage did not affect body weight or activity of liver enzymes and did not show any sign of toxicity in liver, spleen, kidney, lung and heart tissues in mice. Moreover, BD significantly decreased the change in tumor volume over time compared to the control group (p=0.002). BD treatment also markedly decreased the incidence of breast-to-lung cancer metastasis from 67% (control) to 20% (BD) (p<0.05) and the number of metastases from 2.8 (0.0, 48.0) in the control group to 0.0 (0.0, 14.2) in the BD treatment group (p<0.05). Finally, anti-metastatic activity of BD in vivo was further confirmed by the downregulation of expression of PLAU (urokinase plasminogen activator, uPA) and CXCR4 (C-X-C chemokine receptor-4) genes in breast tumors. In conclusion, BD may be considered as a biological therapeutic agent against invasive breast cancers.


Jiang J.,Indiana University | Eliaz I.,Amitabha Medical Clinic and Healing Center | Sliva D.,Indiana University
Integrative Cancer Therapies | Year: 2013

Aim. The objective of this study was to evaluate the combined effect of a known galectin-3 inhibitor, PectaSol-C modified citrus pectin (MCP), and 2 novel integrative polybotanical compounds for breast and prostate health, BreastDefend (BD) and ProstaCaid (PC), on invasive behavior in human breast and prostate cancer cells in vitro, respectively. Methods. The effect of MCP and BD and of MCP and PC on invasiveness was assessed by cell adhesion, cell migration, and cell invasion assays. Secretion of urokinase plasminogen activator (uPA) was determined by Western blot analysis. Results. Although low concentrations of MCP (0.25-1.0 mg/mL) do not suppress cell adhesion of breast or prostate cancer cells, the combination of MCP with BD or PC synergistically inhibits adhesion of these cells. Dose-dependent inhibition of breast and prostate cancer cell migration by MCP (0.25-1.0 mg/mL) is synergistically enhanced by BD (20 μg/mL) and PC (10 μg/mL), respectively. BD or PC did not further inhibit the invasion of breast and prostate cancer cells by MCP; however, the combination of MCP with BD or PC suppressed secretion of uPA from breast and prostate cancer cells, respectively. Conclusion. The combination of MCP with BD and of MCP with PC synergistically inhibits the metastatic phenotypes of human breast and prostate cancer cells, respectively. Further studies confirming these observations in animal models of breast and prostate cancer metastasis are warranted. © The Author(s) 2012.


Cheng S.,South China Agricultural University | Cheng S.,Indiana University | Eliaz I.,Amitabha Medical Clinic and Healing Center | Lin J.,South China Agricultural University | Sliva D.,Indiana University
International Journal of Oncology | Year: 2013

Poria cocos is a medicinal mushroom that is widely used in traditional Asian medicine. Here, we show that a characterized mixture of triterpenes extracted from P. cocos (PTE) and three purified triterpenes: pachymic acid (PA), dehydropachymic acid (DPA) and polyporenic acid C (PPAC) suppress the proliferation of the human pancreatic cancer cell lines Panc-1, MiaPaca-2, AsPc-1 and BxPc-3. Moreover, the most effective compound, PA, only slightly affects the proliferation of HPDE-6 normal pancreatic duct epithelial cells. The anti-proliferative effects of PTE on BxPc-3 cells are mediated by the cell cycle arrest at G0/G1 phase. DNA microarray analysis demonstrated that PTE significantly downregulates the expression of KRAS and matrix metalloproteinase-7 (MMP-7) in BxPc-3 cells. In addition, PTE and PA suppress the invasive behavior of BxPc-3 cells. The inhibition of invasiveness by PTE and PA was associated with the reduction of MMP-7 at the protein level and the role of MMP-7 further confirmed by the gene silencing of MMP-7 which also suppressed the invasiveness of BxPc-3 cells. In conclusion, triterpenes from P. cocos demonstrate anticancer and anti-invasive effects on human pancreatic cancer cells and can be considered as new therapeutic agents in the treatment of pancreatic cancer.


PubMed | Indiana University and Amitabha Medical Clinic and Healing Center
Type: Journal Article | Journal: International journal of oncology | Year: 2016

Honokiol, a biologically active compound isolated from Magnolia bark, has been shown to possess promising anticancer effect through induction of apoptosis. However, there is a relative lack of information regarding its antimetastatic activity. Renal cell carcinoma(RCC) is the most common malignancy of the adult kidney and is known for high risk of metastasis. Clinically, therapeutic methods for metastatic RCC cases are limited and efforts to exploit new treatments are still ongoing. The results of our current investigation first revealed that honokiol suppressed the proliferation of different human RCCs without affecting cell viability. In addition, honokiol inhibited migration of highly metastatic RCC 7860 cells and stimulated the activity of small GTPase, RhoA. Furthermore, phosphorylated myosin light chain(MLC) and excessive formation of actin stress fibers were identified in 7860 cells treated with honokiol. Interestingly, the pharmacological Rhoassociated protein kinase(ROCK) inhibitor Y27632 attenuated contraction of actin stress fibers induced by honokiol and abrogated honokiolmediated inhibition of cell migration. Together these important findings suggest that honokiol suppresses the migration of highly metastatic RCC through activation of RhoA/ROCK/MLC signaling and warrants attention in the treatment of RCC metastasis as a novel therapeutic approach.


Eliaz I.,Amitabha Medical Clinic and Healing Center
Anti-Aging Therapeutics - 2011 Conference Year | Year: 2012

Dr. Isaac Eliaz, a leading researcher of modified citrus pectin (MCP), discusses new research on the role of galectin-3 and MCP in health and disease, and the benefits of MCP as a potent galectin-3 inhibitor. High concentrations of free circulating galectin-3 in the blood are commonly seen in many different cancer patients. Recent studies have shown that changes in circulating galectin-3 levels in cancer patients may contribute significantly to the metastatic spread of cancer cells by enhancing their ability to adhere to blood vessel endothelium and by helping their avoidance of immune surveillance. Furthermore, groundbreaking new research shows that the presence of high galectin-3 levels in the blood is now linked to inflammation, fibrosis, and progressive heart disease, in addition to cancer progression. Thus, galectin-3 can serve as a novel therapeutic target for conditions from metastatic cancer to congestive heart failure and inflammation/fibrosis related illnesses, through the use of galectin-3 antagonists such as MCP. In this article, Dr. Eliaz also explains the application of a new galectin-3 serum assay that has been refined to a high precision enzyme linked immunosorbent assay (ELISA) available through blood screening. This assay, which is FDA approved and covered by most insurances, will allow patients and practitioners to easily determine their levels of circulating galectin-3 as a tool for risk prognosis. Discussion of how to analyze, interpret, and apply these test results in integrative and antiaging medicine is explored. MCP is a complex water soluble polysaccharide obtained from the peel pith of citrus fruits and modified by means of enzymes, ph modification, and temperature treatment in order to obtain the necessary structure for bio-absorption and biological activity. Galectin-3 is a beta-galactoside binding lectin with roles involved in various physiological and pathological processes, including cell growth, adhesion, differentiation, angiogenesis, apoptosis, tumorigenesis, metastasis, inflammation, and fibrosis. By binding to and inhibiting galectin-3, MCP has the ability to affect numerous rate-limiting steps in cancer progression as well as inflammatory and fibrotic diseases. Pre-clinical studies published in 2011 demonstrated that MCP reduced galectin-3 in association with decreased renal fibrosis, macrophages, pro-inflammatory cytokine expression, and apoptosis. At a histological level, MCP clearly reduced renal cell proliferation. This data indicates that MCP is protective in experimental nephropathy with modulation of early proliferation and later galectin-3 expression, apoptosis, and fibrosis. This and other peer-reviewed research indicate that MCP is a novel strategy to reduce inflammation, fibrosis, and cancer occurrence in the long-term, via carbohydrate binding-related functions of galectin-3. These results make MCP a remarkable, long term anti-aging supplement. The research on the multiple ways in which galectin-3 influences specific disease progression is discussed from a clinical perspective. Dr. Eliaz explains how MCP functions to bind to and inhibit galectin- 3 and also discusses research on MCP's therapeutic actions on cancer, immune response, and heavy metal detoxification.


In this case study, I report on a patient with stage IV ovarian cancer and underlying pro-inflammatory comorbidities. Initially, the patient's inflammatory condition was treated with an intensive integrative anti-inflammatory protocol using a combination of oral and intravenous nutrients and botanicals along with pharmaceutical intervention. This was followed by a standard course of chemotherapy supported by an individualized integrative protocol-with excellent response. Galectin-3 levels as well as other inflammatory and tumor markers were monitored throughout the course of treatment. Correlation with other markers, the clinical course of the disease, and symptomatology are presented. Galectin-3, a novel marker with potential clinical importance in cancer progression as well as inflammation and fibrosis, has been extensively researched in multiple in vitro, in vivo, and epidemiological studies. In this paper, a case in which galectin-3 has been used to assess and monitor patient progress is presented for the first time. This case is of further interest because of its complexity, with the coexistence of acute inflammatory conditions combined with progressing metastatic cancer. Galectin-3 monitoring reflected this complexity; nevertheless, it provided useful information and correlation with other inflammatory markers. The results suggest that monitoring serum galectin-3 as a marker for both inflammatory processes and cancer progression to a higher probability of metastasis may have clinical relevance. Additional clinical research is warranted. © 2013 S. Karger AG, Basel.

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