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Rich66 · 05-19-2010, 10:32 PM

(Il-6, Stat 3, Bcl-2, cyclin D1, survivin, w/resveratrol, Hif1 alpha, w/Sorafenib)

PLoS One. 2010 Jul 6;5(7):e11457.
Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines.

Meeran SM, Patel SN, Tollefsbol TO.
Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.

Abstract

BACKGROUND: Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. PRINCIPAL FINDINGS: We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP) analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells. SIGNIFICANCE: Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention.

PMID: 20625516 [PubMed - in process]PMCID: PMC2897894Free PMC Article

Cancer Prev Res (Phila Pa). 2010 Apr;3(4):484-94. Epub 2010 Mar 16.
Sulforaphane inhibits constitutive and interleukin-6-induced activation of signal transducer and activator of transcription 3 in prostate cancer cells.

Hahm ER, Singh SV.
2.32A Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.

Abstract

D,L-sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 micromol/L) decreased constitutive (DU145 cells) and IL-6-induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr(705)) as well as its upstream regulator Janus-activated kinase 2 (Tyr(1007/1008)). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6-induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN. (c) 2010 AACR.

PMID: 20233902 [PubMed - in process]PMCID: PMC2853726 [Available on 2011/4/1]

Neurochem Res. 2010 Jan;35(1):152-61. Epub 2009 Aug 15.
Combination treatment with resveratrol and sulforaphane induces apoptosis in human U251 glioma cells.

Jiang H, Shang X, Wu H, Huang G, Wang Y, Al-Holou S, Gautam SC, Chopp M.
Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. hjiang1@hfhs.org

Abstract

Resveratrol is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Sulforaphane belongs to the family of isothiocyanates and is highly enriched in cruciferous vegetables. Our previous study showed that resveratrol, when used at high concentrations, inhibited cell proliferation, caused the cell cycle arrest and induced apoptotic cell death in glioma cells. In the current study, we tested the effect of combination treatment with resveratrol and sulforaphane, when both were used at low concentrations, on cell proliferation, migration and death in human U251 glioma cells. Our study shows that combination treatment with resveratrol and sulforaphane inhibits cell proliferation and migration, reduces cell viability, induces lactate dehydrogenase release, decreases pro-survival Akt phosphorylation and increases caspase-3 activation. The use of combination of bioactive food components, such as resveratrol and sulforaphane, may be a viable approach for the treatment of glioma.

PMID: 19685289 [PubMed - indexed for MEDLINE]PMCID: PMC2821708Free PMC Article

Mutat Res. 2007 May-Jun;635(2-3):90-104. Epub 2006 Nov 28.
Sulforaphane as a promising molecule for fighting cancer.

Fimognari C, Hrelia P.
Department of Pharmacology, University of Bologna, Bologna, Italy. carmela.fimognari@unibo.it
Abstract

A number of natural compounds with inhibitory effects on tumorigenesis have been identified from our diet. Several studies have documented the cancer-preventive activity of a significant number of isothiocyanates (ITCs), the majority of which occur in plants, especially in Cruciferous vegetables. The most characterized ITC is sulforaphane (SFN). SFN has received a great deal of attention because of its ability to simultaneously modulate multiple cellular targets involved in cancer development, including: (i) DNA protection by modulating carcinogen-metabolizing enzymes and blocking the action of mutagens; (ii) inhibition of cell proliferation and induction of apoptosis, thereby retarding or eliminating clonal expansion of initiated, transformed, and/or neoplastic cells; (iii) inhibition of neoangiogenesis, progression of benign tumors to malignant tumors, and metastasis formation. SFN is therefore able to prevent, delay, or reverse preneoplastic lesions, as well as to act on cancer cells as a therapeutic agent. Taking into account this evidence and its favorable toxicological profile, SFN can be viewed as a conceptually promising agent in cancer prevention and/or therapy.

PMID: 17134937 [PubMed - indexed for MEDLINE]

Int J Cancer. 2008 Sep 15;123(6):1255-61.
Sulforaphane inhibited expression of hypoxia-inducible factor-1alpha in human tongue squamous cancer cells and prostate cancer cells.

Yao H, Wang H, Zhang Z, Jiang BH, Luo J, Shi X.
Graduate Center for Toxicology, College of Medicine, The University of Kentucky, Lexington, KY 40503, USA.
Abstract

Previous studies show that a number of natural compounds from our diet have anticancer effects. Sulforaphane is the most characterized isothiocyanates (ITCs), which are identified in cruciferous vegetables. Sulforaphane is viewed as a conceptually promising agent in cancer prevention. Because of its ability to induce cancer cell apoptosis, it inhibits progression of benign tumors to malignant tumors and interrupts metastasis. However, the effect of sulforaphane on tongue cancer cell proliferation has not yet been reported, and the mechanisms that sulforaphane inhibits cancer development are still unclear. Hypoxia-inducible factor 1 (HIF-1) expression is associated with tumorigenesis and angiogenesis. It regulates the expression of many genes including vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, and lactate dehydrogenase A. In our study, we investigated the effects of sulforaphane on expression of hypoxia-inducible factor-1alpha (HIF-1alpha), which was overexpressed in many human malignant tumors, human tongue squamous cell carcinoma and prostate cancer DU145 cells. Sulforaphane inhibited hypoxia induced expression of HIF-1alpha via inhibiting synthesis of HIF-1alpha. Sulforaphane was also found to inhibit hypoxia induced HIF-1alpha expression through activating JNK and ERK signaling pathways, but not AKT pathway. Inhibition of HIF-1alpha by sulforaphane resulted in decreasing expression of VEGF. Taken together, these results suggest that sulforaphane is an effective chemopreventive compound against tongue cancers and prostate cell angiogenesis in vitro, and that the HIF-1alpha target provides a new sight into the mechanisms of sulforaphane's inhibition against tumor cell proliferation. Copyright 2008 Wiley-Liss, Inc.

PMID: 18561315 [PubMed - indexed for MEDLINE]

Cancer Res. 2010 Jun 8. [Epub ahead of print]
Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics.

Rausch V, Liu L, Kallifatidis G, Baumann B, Mattern J, Gladkich J, Wirth T, Schemmer P, Büchler MW, Zöller M, Salnikov AV, Herr I.
Authors' Affiliations: Molecular OncoSurgery and Tumor Cell Biology, University of Heidelberg and German Cancer Research Center; Department of General Surgery, University of Heidelberg; Translational Immunology Unit, German Cancer Research Center, Heidelberg, Germany; and Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Abstract

Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappaB associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappaB activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappaB binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO. Cancer Res; 70(12); 5004-13. (c)2010 AACR.

PMID: 20530687 [PubMed - as supplied by publisher]

Raw broccoli doubles survival in bladder cancer patients
Jacob Schor, ND, FABNO
July 1, 2010

An interesting paper came out a few weeks ago of particular interest to people with bladder cancer but that is worth all of us noticing. The paper is the latest in a sequence of papers authored by Li Tang and colleagues at the Roswell Cancer Research Center in New York.

Tang has been studying the effect of cruciferous vegetables on bladder cancer for years. In 2004, Tang reported that cruciferous vegetables inhibit the growth of human bladder cancer cells in 2004. [1]

In 2008, Tang, using data from a hospital based case-controlled study, reported that consumption of raw cruciferous vegetables lowered the risk of getting bladder cancer. They found a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64). In the early study, as in the current study, no significant benefit was found for fruit, total vegetables, or cooked cruciferous vegetable consumption. Only eating raw cruciferous vegetables provided protection. [2]

In a February 2010 paper, Tang reported that the isothiocyanates found in cruciferous vegetables inhibited the growth of bladder tumor cells in a rat model of human bladder cancer. [3]

The results of Tang’s current paper are fully congruent with the earlier findings.

Tang’s most recent paper was published June 15. In this paper, data from the Roswell Park Cancer Institute’s Tumor Registry, patient medical records, and routinely collected questionnaire data, were analyzed for potential associations between intake of cruciferous vegetables and survival among bladder cancer patients.

A total of 239 bladder cancer patients were included in the study. After an average of 8 years of follow-up, 179 deaths occurred, with 101 deaths attributable to bladder cancer.

Analysis of the data revealed a strong and statistically significant inverse association between raw broccoli intake and bladder cancer mortality. Those eating one or more servings of raw broccoli a month compared to those eating less than one serving a month reduced their chance of dying from bladder cancer by 57% and reduced the risk of dying from all causes by 45%. No significant associations were found in the data for total vegetables, total fruits or for other individual cruciferous vegetables. [4]

These effects, though striking, are entirely plausible. Consumption of cruciferous vegetables is associated with reduced risk of bladder cancer. These plants contain a number of chemopreventive agents, including isothiocyanates. Isothiocyanate metabolites that reach the bladder still retain their anti-cancer action. They concentrate in the urine, reaching levels two to three times higher in the bladder than in the blood serum. Cooking lowers isothiocyanate levels: urinary levels are 3-4 times higher after eating raw broccoli than cooked broccoli. Broccoli contains higher levels of isothiocyanates than any other cruciferous vegetable, 40% more than cabbage and more than double the amount found in cauliflower. The type of isothiocyanate found varies with type of vegetable. In broccoli, the major isothiocyanate is sulforaphane; cabbage and cauliflower contain allyl isothiocyanate.

It is not just in bladder cancer where raw is better. Li Tang had another important study published in April 2010 that reported cruciferous vegetable consumption lowers the risk of lung cancer in smokers. Only consumption of raw cruciferous vegetables had a statistically significantly effect on lung cancer risk, those smokers in the middle tertile of consumption had half the risk of those in the lower tertile. [5]

These studies give us good reason to be more specific in what we tell our patients. Not only should we encourage patient to eat cruciferous vegetables, but we should tell them to eat broccoli and make a point to eat it raw.

Bottom Line:
1. Raw broccoli significantly halves the risk of dying for people who have had bladder cancer from any cause but particularly from bladder cancer.
2. Raw broccoli is more effective than cooked broccoli.
3. Broccoli is more effective than other cruciferous vegetables.
4. Raw broccoli protects against other cancers such as lung cancer in smokers.

Cancer Prev Res (Phila Pa). 2010 Apr;3(4):484-94. Epub 2010 Mar 16.
Sulforaphane inhibits constitutive and interleukin-6-induced activation of signal transducer and activator of transcription 3 in prostate cancer cells.

Hahm ER, Singh SV.
2.32A Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA.

purchase TEXT

Abstract

D,L-sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 micromol/L) decreased constitutive (DU145 cells) and IL-6-induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr(705)) as well as its upstream regulator Janus-activated kinase 2 (Tyr(1007/1008)). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6-induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN.

PMID: 20233902 [PubMed - indexed for MEDLINE]PMCID: PMC2853726 [Available on 2011/4/1]

J Biol Chem. 2010 Sep 10. [Epub ahead of print]
Sulforaphane activates heat shock response and enhances proteasome activity through upregulation of HSP27.
Gan N, Wu YC, Brunet M, Garrido C, Chung FL, Dai C, Mi L.
Georegtown University Medical Center, United States;

FREE TEXT

Abstract
It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid beta-induced cytotoxicity. Here we report that SFN activates heat shock transcription factor 1 (Hsf1)-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells while absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection.

PMID: 20833711 [PubMed - as supplied by publisher]Free Article

05-19-2010, 10:32 PM	#3
Rich66 Senior Member Join Date: Feb 2008 Location: South East Wisconsin Posts: 3,431	Re: Sulforaphane (from broccoli) (Il-6, Stat 3, Bcl-2, cyclin D1, survivin, w/resveratrol, Hif1 alpha, w/Sorafenib) PLoS One. 2010 Jul 6;5(7):e11457. Sulforaphane causes epigenetic repression of hTERT expression in human breast cancer cell lines. Meeran SM, Patel SN, Tollefsbol TO. Department of Biology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America. Abstract BACKGROUND: Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a common dietary component that has histone deacetylase inhibition activity and exciting potential in cancer prevention. The mechanisms by which SFN imparts its chemopreventive properties are of considerable interest and little is known of its preventive potential for breast cancer. PRINCIPAL FINDINGS: We found that SFN significantly inhibits the viability and proliferation of breast cancer cells in vitro while it has negligible effects on normal breast cells. Inhibition of telomerase has received considerable attention because of its high expression in cancer cells and extremely low level of expression in normal cells. SFN treatment dose- and time-dependently inhibited human telomerase reverse transcriptase (hTERT), the catalytic regulatory subunit of telomerase, in both MCF-7 and MDA-MB-231 human breast cancer cells. DNA methyltransferases (DNMTs), especially DNMT1 and DNMT3a, were also decreased in SFN-treated breast cancer cells suggesting that SFN may repress hTERT by impacting epigenetic pathways. Down-regulation of DNMTs in response to SFN induced site-specific CpG demethylation occurring primarily in the first exon of the hTERT gene thereby facilitating CTCF binding associated with hTERT repression. Chromatin immunoprecipitation (ChIP) analysis of the hTERT promoter revealed that SFN increased the level of active chromatin markers acetyl-H3, acetyl-H3K9 and acetyl-H4, whereas the trimethyl-H3K9 and trimethyl-H3K27 inactive chromatin markers were decreased in a dose-dependent manner. SFN-induced hyperacetylation facilitated the binding of many hTERT repressor proteins such as MAD1 and CTCF to the hTERT regulatory region. Depletion of CTCF using siRNA reduced the SFN-induced down-regulation of hTERT mRNA transcription in these breast cancer cells. In addition, down-regulation of hTERT expression facilitated the induction of cellular apoptosis in human breast cancer cells. SIGNIFICANCE: Collectively, our results provide novel insights into SFN-mediated epigenetic down-regulation of telomerase in breast cancer prevention and may open new avenues for approaches to SFN-mediated cancer prevention. PMID: 20625516 [PubMed - in process]PMCID: PMC2897894Free PMC Article Cancer Prev Res (Phila Pa). 2010 Apr;3(4):484-94. Epub 2010 Mar 16. Sulforaphane inhibits constitutive and interleukin-6-induced activation of signal transducer and activator of transcription 3 in prostate cancer cells. Hahm ER, Singh SV. 2.32A Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. Abstract D,L-sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 micromol/L) decreased constitutive (DU145 cells) and IL-6-induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr(705)) as well as its upstream regulator Janus-activated kinase 2 (Tyr(1007/1008)). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6-induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN. (c) 2010 AACR. PMID: 20233902 [PubMed - in process]PMCID: PMC2853726 [Available on 2011/4/1] Neurochem Res. 2010 Jan;35(1):152-61. Epub 2009 Aug 15. Combination treatment with resveratrol and sulforaphane induces apoptosis in human U251 glioma cells. Jiang H, Shang X, Wu H, Huang G, Wang Y, Al-Holou S, Gautam SC, Chopp M. Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA. hjiang1@hfhs.org Abstract Resveratrol is a naturally occurring polyphenolic compound highly enriched in grapes, peanuts, red wine, and a variety of food sources. Sulforaphane belongs to the family of isothiocyanates and is highly enriched in cruciferous vegetables. Our previous study showed that resveratrol, when used at high concentrations, inhibited cell proliferation, caused the cell cycle arrest and induced apoptotic cell death in glioma cells. In the current study, we tested the effect of combination treatment with resveratrol and sulforaphane, when both were used at low concentrations, on cell proliferation, migration and death in human U251 glioma cells. Our study shows that combination treatment with resveratrol and sulforaphane inhibits cell proliferation and migration, reduces cell viability, induces lactate dehydrogenase release, decreases pro-survival Akt phosphorylation and increases caspase-3 activation. The use of combination of bioactive food components, such as resveratrol and sulforaphane, may be a viable approach for the treatment of glioma. PMID: 19685289 [PubMed - indexed for MEDLINE]PMCID: PMC2821708Free PMC Article Mutat Res. 2007 May-Jun;635(2-3):90-104. Epub 2006 Nov 28. Sulforaphane as a promising molecule for fighting cancer. Fimognari C, Hrelia P. Department of Pharmacology, University of Bologna, Bologna, Italy. carmela.fimognari@unibo.it Abstract A number of natural compounds with inhibitory effects on tumorigenesis have been identified from our diet. Several studies have documented the cancer-preventive activity of a significant number of isothiocyanates (ITCs), the majority of which occur in plants, especially in Cruciferous vegetables. The most characterized ITC is sulforaphane (SFN). SFN has received a great deal of attention because of its ability to simultaneously modulate multiple cellular targets involved in cancer development, including: (i) DNA protection by modulating carcinogen-metabolizing enzymes and blocking the action of mutagens; (ii) inhibition of cell proliferation and induction of apoptosis, thereby retarding or eliminating clonal expansion of initiated, transformed, and/or neoplastic cells; (iii) inhibition of neoangiogenesis, progression of benign tumors to malignant tumors, and metastasis formation. SFN is therefore able to prevent, delay, or reverse preneoplastic lesions, as well as to act on cancer cells as a therapeutic agent. Taking into account this evidence and its favorable toxicological profile, SFN can be viewed as a conceptually promising agent in cancer prevention and/or therapy. PMID: 17134937 [PubMed - indexed for MEDLINE] Int J Cancer. 2008 Sep 15;123(6):1255-61. Sulforaphane inhibited expression of hypoxia-inducible factor-1alpha in human tongue squamous cancer cells and prostate cancer cells. Yao H, Wang H, Zhang Z, Jiang BH, Luo J, Shi X. Graduate Center for Toxicology, College of Medicine, The University of Kentucky, Lexington, KY 40503, USA. Abstract Previous studies show that a number of natural compounds from our diet have anticancer effects. Sulforaphane is the most characterized isothiocyanates (ITCs), which are identified in cruciferous vegetables. Sulforaphane is viewed as a conceptually promising agent in cancer prevention. Because of its ability to induce cancer cell apoptosis, it inhibits progression of benign tumors to malignant tumors and interrupts metastasis. However, the effect of sulforaphane on tongue cancer cell proliferation has not yet been reported, and the mechanisms that sulforaphane inhibits cancer development are still unclear. Hypoxia-inducible factor 1 (HIF-1) expression is associated with tumorigenesis and angiogenesis. It regulates the expression of many genes including vascular endothelial growth factor (VEGF), inducible nitric oxide synthase, and lactate dehydrogenase A. In our study, we investigated the effects of sulforaphane on expression of hypoxia-inducible factor-1alpha (HIF-1alpha), which was overexpressed in many human malignant tumors, human tongue squamous cell carcinoma and prostate cancer DU145 cells. Sulforaphane inhibited hypoxia induced expression of HIF-1alpha via inhibiting synthesis of HIF-1alpha. Sulforaphane was also found to inhibit hypoxia induced HIF-1alpha expression through activating JNK and ERK signaling pathways, but not AKT pathway. Inhibition of HIF-1alpha by sulforaphane resulted in decreasing expression of VEGF. Taken together, these results suggest that sulforaphane is an effective chemopreventive compound against tongue cancers and prostate cell angiogenesis in vitro, and that the HIF-1alpha target provides a new sight into the mechanisms of sulforaphane's inhibition against tumor cell proliferation. Copyright 2008 Wiley-Liss, Inc. PMID: 18561315 [PubMed - indexed for MEDLINE] Cancer Res. 2010 Jun 8. [Epub ahead of print] Synergistic Activity of Sorafenib and Sulforaphane Abolishes Pancreatic Cancer Stem Cell Characteristics. Rausch V, Liu L, Kallifatidis G, Baumann B, Mattern J, Gladkich J, Wirth T, Schemmer P, Büchler MW, Zöller M, Salnikov AV, Herr I. Authors' Affiliations: Molecular OncoSurgery and Tumor Cell Biology, University of Heidelberg and German Cancer Research Center; Department of General Surgery, University of Heidelberg; Translational Immunology Unit, German Cancer Research Center, Heidelberg, Germany; and Institute of Physiological Chemistry, University of Ulm, Ulm, Germany. Abstract Recent evidence suggests that pancreatic cancer and other solid tumors contain a subset of tumorigenic cells capable of extensive self-renewal that contribute to metastasis and treatment resistance. Sorafenib (SO) is a promising new multikinase inhibitor for treatment of advanced kidney and liver cancers. We report here targeting of pancreatic cancer stem cells (CSC) by SO and the development of a strategy to enhance this effect. Although SO administration diminished clonogenicity, spheroid formation, aldehyde dehydrogenase 1 (ALDH1) activity, growth on immunodeficient mice, proliferation, and angiogenesis and induced apoptosis, we observed SO-induced activation of NF-kappaB associated with survival and regrowth of spheroids. For enhanced elimination of CSC characteristics by SO, we cotreated cells with sulforaphane (SF). This broccoli isothiocyanate was recently described to eliminate pancreatic CSCs by downregulation of NF-kappaB activity without inducing toxic side effects. On combination treatment, SF completely eradicated SO-induced NF-kappaB binding, which was associated with abrogated clonogenicity, spheroid formation, ALDH1 activity, migratory capacity, and induction of apoptosis. In vivo, combination therapy reduced the tumor size in a synergistic manner. This was due to induction of apoptosis, inhibition of proliferation and angiogenesis, and downregulation of SO-induced expression of proteins involved in epithelial-mesenchymal transition. Our data suggest that SF may be suited to increase targeting of CSCs by SO. Cancer Res; 70(12); 5004-13. (c)2010 AACR. PMID: 20530687 [PubMed - as supplied by publisher] Raw broccoli doubles survival in bladder cancer patients Jacob Schor, ND, FABNO July 1, 2010 An interesting paper came out a few weeks ago of particular interest to people with bladder cancer but that is worth all of us noticing. The paper is the latest in a sequence of papers authored by Li Tang and colleagues at the Roswell Cancer Research Center in New York. Tang has been studying the effect of cruciferous vegetables on bladder cancer for years. In 2004, Tang reported that cruciferous vegetables inhibit the growth of human bladder cancer cells in 2004. [1] In 2008, Tang, using data from a hospital based case-controlled study, reported that consumption of raw cruciferous vegetables lowered the risk of getting bladder cancer. They found a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64). In the early study, as in the current study, no significant benefit was found for fruit, total vegetables, or cooked cruciferous vegetable consumption. Only eating raw cruciferous vegetables provided protection. [2] In a February 2010 paper, Tang reported that the isothiocyanates found in cruciferous vegetables inhibited the growth of bladder tumor cells in a rat model of human bladder cancer. [3] The results of Tang’s current paper are fully congruent with the earlier findings. Tang’s most recent paper was published June 15. In this paper, data from the Roswell Park Cancer Institute’s Tumor Registry, patient medical records, and routinely collected questionnaire data, were analyzed for potential associations between intake of cruciferous vegetables and survival among bladder cancer patients. A total of 239 bladder cancer patients were included in the study. After an average of 8 years of follow-up, 179 deaths occurred, with 101 deaths attributable to bladder cancer. Analysis of the data revealed a strong and statistically significant inverse association between raw broccoli intake and bladder cancer mortality. Those eating one or more servings of raw broccoli a month compared to those eating less than one serving a month reduced their chance of dying from bladder cancer by 57% and reduced the risk of dying from all causes by 45%. No significant associations were found in the data for total vegetables, total fruits or for other individual cruciferous vegetables. [4] These effects, though striking, are entirely plausible. Consumption of cruciferous vegetables is associated with reduced risk of bladder cancer. These plants contain a number of chemopreventive agents, including isothiocyanates. Isothiocyanate metabolites that reach the bladder still retain their anti-cancer action. They concentrate in the urine, reaching levels two to three times higher in the bladder than in the blood serum. Cooking lowers isothiocyanate levels: urinary levels are 3-4 times higher after eating raw broccoli than cooked broccoli. Broccoli contains higher levels of isothiocyanates than any other cruciferous vegetable, 40% more than cabbage and more than double the amount found in cauliflower. The type of isothiocyanate found varies with type of vegetable. In broccoli, the major isothiocyanate is sulforaphane; cabbage and cauliflower contain allyl isothiocyanate. It is not just in bladder cancer where raw is better. Li Tang had another important study published in April 2010 that reported cruciferous vegetable consumption lowers the risk of lung cancer in smokers. Only consumption of raw cruciferous vegetables had a statistically significantly effect on lung cancer risk, those smokers in the middle tertile of consumption had half the risk of those in the lower tertile. [5] These studies give us good reason to be more specific in what we tell our patients. Not only should we encourage patient to eat cruciferous vegetables, but we should tell them to eat broccoli and make a point to eat it raw. Bottom Line: 1. Raw broccoli significantly halves the risk of dying for people who have had bladder cancer from any cause but particularly from bladder cancer. 2. Raw broccoli is more effective than cooked broccoli. 3. Broccoli is more effective than other cruciferous vegetables. 4. Raw broccoli protects against other cancers such as lung cancer in smokers. Cancer Prev Res (Phila Pa). 2010 Apr;3(4):484-94. Epub 2010 Mar 16. Sulforaphane inhibits constitutive and interleukin-6-induced activation of signal transducer and activator of transcription 3 in prostate cancer cells. Hahm ER, Singh SV. 2.32A Hillman Cancer Center Research Pavilion, University of Pittsburgh Cancer Institute, 5117 Centre Avenue, Pittsburgh, PA 15213, USA. purchase TEXT Abstract D,L-sulforaphane (SFN), a synthetic analogue of broccoli-derived L-isomer, inhibits viability of human prostate cancer cells and prevents development of prostate cancer and distant site metastasis in a transgenic mouse model. However, the mechanism underlying the anticancer effect of SFN is not fully understood. We now show that SFN inhibits constitutive and interleukin-6 (IL-6)-inducible activation of signal transducer and activator of transcription 3 (STAT3), which is an oncogenic transcription factor activated in many human malignancies, including prostate cancer. Growth-suppressive concentrations of SFN (20 and 40 micromol/L) decreased constitutive (DU145 cells) and IL-6-induced (DU145 and LNCaP cells) phosphorylation of STAT3 (Tyr(705)) as well as its upstream regulator Janus-activated kinase 2 (Tyr(1007/1008)). Exposure of DU145 and LNCaP cells to SFN resulted in suppression of (a) IL-6-induced transcriptional activity of STAT3 as judged by luciferase reporter assay and (b) nuclear translocation of phospho-STAT3 as revealed by immunofluorescence microscopy. Levels of many STAT3-regulated gene products, including Bcl-2, cyclin D1, and survivin, were also reduced in SFN-treated cells. The IL-6-mediated activation of STAT3 conferred partial but marked protection against SFN-induced apoptosis as evidenced by cytoplasmic histone-associated DNA fragmentation and cleavage of poly(ADP-ribose) polymerase and procaspase-3. Furthermore, knockdown of STAT3 protein using small interfering RNA resulted in a modest yet statistically significant increase in SFN-induced apoptotic DNA fragmentation in DU145 cells. Suppression of STAT3 activation was also observed in cells treated with naturally occurring analogues of SFN. In conclusion, the present study indicates that inhibition of STAT3 partially contributes to the proapoptotic effect of SFN. PMID: 20233902 [PubMed - indexed for MEDLINE]PMCID: PMC2853726 [Available on 2011/4/1] J Biol Chem. 2010 Sep 10. [Epub ahead of print] Sulforaphane activates heat shock response and enhances proteasome activity through upregulation of HSP27. Gan N, Wu YC, Brunet M, Garrido C, Chung FL, Dai C, Mi L. Georegtown University Medical Center, United States; FREE TEXT Abstract It is conceivable that stimulating proteasome activity for rapid removal of misfolded and oxidized proteins is a promising strategy to prevent and alleviate aging-related diseases. Sulforaphane (SFN), an effective cancer preventive agent derived from cruciferous vegetables, has been shown to enhance proteasome activities in mammalian cells and to reduce the level of oxidized proteins and amyloid beta-induced cytotoxicity. Here we report that SFN activates heat shock transcription factor 1 (Hsf1)-mediated heat shock response. Specifically, SFN-induced expression of heat shock protein 27 (Hsp27) underlies SFN-stimulated proteasome activity. SFN-induced proteasome activity was significantly enhanced in Hsp27-overexpressing cells while absent in Hsp27-silenced cells. The role of Hsp27 in regulating proteasome activity was further confirmed in isogenic REG cells in which SFN-induced proteasome activation was only observed in cells stably overexpressing Hsp27, but not in the Hsp27-free parental cells. Finally, we demonstrated that phosphorylation of Hsp27 is irrelevant to SFN-induced proteasome activation. This study provides a novel mechanism underlying SFN-induced proteasome activity. This is the first report that heat shock response by SFN, in addition to the antioxidant response mediated by the Keap1-Nrf2 pathway, may contribute to cytoprotection. PMID: 20833711 [PubMed - as supplied by publisher]Free Article __________________ Mom's treatment history (link)