(ellagic acid, Omega5, NF-kB inhib, antiaromatase/SERM, anti-proliferative, apoptotic, effects blocked by VitE & PKC inhibs, dose dependendent on ER?, interfere with anti her2?)
Pomegranate Fruit Extract Impairs Invasion and Motility in Human Breast Cancer
Gazala N. Khan Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA, gkhan@umich.edu
Michael A. Gorin
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Devin Rosenthal
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Quintin Pan
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Li Wei Bao
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Zhi Fen Wu
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Robert A. Newman
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston,TX, USA, Punisyn Pharmaceuticals, Haifa, Israel
Alison D. Pawlus
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston,TX, USA
Peiying Yang
Department of Experimental Therapeutics, M.D. Anderson Cancer Center, Houston,TX, USA
Ephraim P. Lansky
Punisyn Pharmaceuticals, Haifa, Israel
Sofia D. Merajver
Department of Internal Medicine, University of Michigan,Ann Arbor, MI, USA
Purpose. Pomegranate fruit extracts (PFEs) possess polyphenolic and other compounds with antiproliferative, pro-apoptotic and anti-inflammatory effects in prostate, lung, and other cancers. Because nuclear transcription factor-kB (NF-kB) is known to regulate cell survival, proliferation, tumorigenesis, and inflammation, it was postulated that PFEs may exert anticancer effects at least in part by modulating NF-kB activity.
Experimental design. The authors investigated the effect of a novel, defined PFE consisting of both fermented juice and seed oil on the NF-kB pathway, which is constitutively active in aggressive breast cancer cell lines. The effects of the PFE on NF-kB—regulated cellular processes such as cell survival, proliferation, and invasion were also examined.
Results. Analytical characterization of the bioactive components of the PFE revealed active constituents, mainly ellagitannins and phenolic acids in the aqueous PFE and conjugated octadecatrienoic acids in the lipid PFE derived from seeds.
The aqueous PFE dose-dependently inhibited NF-kB—dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression. Conclusion. Inhibition of motility and invasion by PFEs, coincident with suppressed RhoC and RhoA protein expression, suggests a role for these defined extracts in lowering the metastatic potential of aggressive breast cancer species.
Integrative Cancer Therapies, Vol. 8, No. 3, 242-253 (2009)
DOI: 10.1177/1534735409341405
NEEDS TO BE HIGH ENOUGH TO BE BENEFICIAL?
Endocr Res. 2010 Jan;35(1):1-16.
Pomegranate (Punica granatum) seed linolenic acid isomers: concentration-dependent modulation of estrogen receptor activity.
Tran HN,
Bae SY,
Song BH,
Lee BH,
Bae YS,
Kim YH,
Lansky EP,
Newman RA.
Department of Experimental Therapeutics, Kyungpook National University, Taegu, Republic of Korea.
Abstract
Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 microM, ERbeta at 8.8 microM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 microM.
PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 microM, antagonizing at 101/80 microM. AEA antagonized ERalpha/ERbeta at 150/140 microM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.
PMID: 20136514 [PubMed - indexed for MEDLINE]
Pomegranate fruit extract impairs invasion and motility in human breast cancer
Integrative Cancer Therapies , 10/12/09
Khan GN et al. – Inhibition of motility and invasion by PFEs, coincident with suppressed RhoC and RhoA protein expression, suggests a role for these defined extracts in lowering the metastatic potential of aggressive breast cancer species.
Methods- Investigated effect of novel, defined PFE consisting of both fermented juice and seed oil on NF-kB pathway, which is constitutively active in aggressive breast cancer cell lines
- Effects of PFE on NF-kB—regulated cellular processes such as cell survival, proliferation, and invasion also examined
Results- Analytical characterization of bioactive components of PFE revealed active constituents, mainly ellagitannins and phenolic acids in aqueous PFE and conjugated octadecatrienoic acids in lipid PFE derived from seed
- Aqueous PFE dose-dependently inhibited NF-kB—dependent reporter gene expression associated with proliferation, invasion, and motility in aggressive breast cancer phenotypes while decreasing RhoC and RhoA protein expression
Breast Cancer (Auckl). 2011;5:143-54. Epub 2011 Jul 12.
Delphinidin Inhibits HER2 and Erk1/2 Signaling and Suppresses Growth of HER2-Overexpressing and Triple Negative Breast Cancer Cell Lines.
Ozbay T,
Nahta R.
Source
Departments of Pharmacology.
Abstract
Delphinidin is a polyphenolic compound found in many brightly colored fruits and vegetables. Delphinidin is also the major bioactive component found in many dietary supplements that are currently consumed as complementary cancer medicine including pomegranate extract. The purpose of the current study was to determine the in vitro biological effects of delphinidin on established
breast cancer cell lines of varying molecular subtypes in comparison to non-transformed
breast epithelial cells. We examined cell proliferation, apoptosis, and growth inhibition in response to delphinidin using a tetrazolium salt-based assay, DNA fragmentation assay, and anchorage-independent growth assay. In comparison to vehicle control,
delphinidin inhibited proliferation (P < 0.05), blocked anchorage-independent growth (P < 0.05), and induced apoptosis (P < 0.05) of ER-positive, triple negative, and HER2-overexpressing breast cancer cell lines with limited toxicity to non-transformed breast epithelial cells. MAPK signaling was partially reduced in triple negative cells and ER-negative chemically transformed MCF10A cells after treatment with delphinidin. In addition, delphinidin induced a significant level of apoptosis in HER2-overexpressing cells in association with reduced HER2 and MAPK signaling. Since delphinidin is often consumed as a complementary
cancer medicine, the effect of delphinidin on response to specific HER2-targeted
breast cancer therapies was examined by proliferation assay. Results of
these drug combination studies suggested potential antagonism between delphinidin and HER2-directed treatments. In summary, the
data presented here suggest that single agent delphinidin exhibits growth inhibitory activity in breast cancer cells of various molecular subtypes, but raise concerns regarding potential drug antagonism when used in combination with existing targeted therapies in HER2-overexpressing breast cancer.
- PMID:
- 21792311
- [PubMed - in process]
Cancer Prev Res (Phila Pa). 2010 Jan;3(1):108-13.
Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro.
Adams LS,
Zhang Y,
Seeram NP,
Heber D,
Chen S.
Beckman Research Institute of the City of Hope, Duarte, California, USA.
Estrogen stimulates the proliferation of breast cancer cells and the growth of estrogen-responsive tumors. The aromatase enzyme, which converts androgen to estrogen, plays a key role in breast carcinogenesis.
The pomegranate fruit, a rich source of ellagitannins (ET), has attracted recent attention due to its anticancer and antiatherosclerotic properties.
On consumption, pomegranate ETs hydrolyze, releasing ellagic acid, which is then converted to 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one ("urolithin") derivatives by gut microflora. The purpose of this study was to investigate the antiaromatase activity and inhibition of testosterone-induced breast cancer cell proliferation by ET-derived compounds isolated from pomegranates.
A panel of 10 ET-derived compounds including ellagic acid, gallagic acid, and urolithins A and B (and their acetylated, methylated, and sulfated analogues prepared in our laboratory) were examined for their ability to inhibit aromatase activity and testosterone-induced breast cancer cell proliferation. Using a microsomal aromatase assay, we screened the panel of ET-derived compounds and identified six with antiaromatase activity. Among these,
urolithin B (UB) was shown to most effectively inhibit aromatase activity in a live cell assay. Kinetic analysis of UB showed mixed inhibition, suggesting more than one inhibitory mechanism. Proliferation assays also determined that UB significantly inhibited testosterone-induced MCF-7aro cell proliferation. The remaining test compounds also exhibited antiproliferative activity, but to a lesser degree than UB. These studies suggest that pomegranate ET-derived compounds have potential for the prevention of estrogen-responsive breast cancers.
PMID: 20051378 [PubMed - in process]
Int J Oncol. 2010 Feb;36(2):421-6.
Punicic acid is an omega-5 fatty acid capable of inhibiting breast cancer proliferation.
Grossmann ME,
Mizuno NK,
Schuster T,
Cleary MP.
University of Minnesota, Hormel Institute, Austin, MN 55912-3679, USA.
Pomegranate extracts have been used as anticancer agents and they contain a large number of potentially bioactive substances. Punicic acid is an omega-5 long chain polyunsaturated fatty acid found in Punica granatum (pomegranate) seed oil. A number of long chain fatty acids have been reported to have cancer preventive actions. Here we
investigated the potential ability of punicic acid to affect growth of both an estrogen insensitive breast cancer cell line (MDA-MB-231) and an estrogen sensitive cell line developed from the MDA-MB-231 cells (MDA-ERalpha7).
Proliferation was inhibited 92 and 96% for MDA-MB-231 and MDA-ERalpha7 cells, respectively compared to untreated cells by 40 microM punicic acid. Furthermore, punicic acid induced apoptosis in the MDA-MB-231 and MDA-ERalpha7 cells by 86 and 91%, respectively compared to untreated control cells and disrupted cellular mitochondrial membrane potential.
We also investigated whether lipid oxidation was required for the function of punicic acid by adding 20 microM of the antioxidant tocotrienol to the assays. This resulted in reversal of the effects of punicic acid on proliferation inhibition, apoptosis and disruption of the mitochondrial membrane potential. Finally,
we evaluated the role of PKC signaling in the anti-cancer effects of punicic acid by performing proliferation assays in the presence of the PKC inhibitor bisindolymaleimide I. Proliferation inhibition by punicic acid was partially blocked in both the MDA-MB-231 and MDA-ERalpha7 cells. These results suggest that
punicic acid has breast cancer inhibitor properties that are dependent on lipid peroxidation and the PKC pathway.
PMID: 20043077 [PubMed - in process]
Endocr Res. 2010 Jan;35(1):1-16.
Pomegranate (Punica granatum) Seed Linolenic Acid Isomers: Concentration-Dependent Modulation of Estrogen Receptor Activity.
Tran HN,
Bae SY,
Song BH,
Lee BH,
Bae YS,
Kim YH,
Lansky EP,
Newman RA.
Department of Experimental Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA; Punisyn Pharmaceuticals, Ltd., Haifa, Israel.
Pomegranate (Punica granatum) seed linolenic acid isomers were evaluated as selective estrogen receptor modulators (SERMs) in vitro. Punicic acid (PA) inhibited (IC(50)) estrogen receptor (ER) alpha at 7.2 muM, ERbeta at 8.8 muM; alpha-eleostearic acid (AEA) inhibited ERalpha/ERbeta at 6.5/7.8 muM. PA (not AEA) agonized ERalpha/ERbeta (EC(50)) at 1.8/2 muM, antagonizing at 101/80 muM. AEA antagonized ERalpha/ERbeta at 150/140 muM. PA and AEA induced ERalpha and ERbeta mRNA expression in MCF-7, but not in MDA-MB-231. Overall, the results show PA and AEA are SERMs.
PMID: 20136514 [PubMed - in process]
Cancer Prev Res (Phila Pa). 2010 Jan;3(1):108-13.
Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro.
Adams LS,
Zhang Y,
Seeram NP,
Heber D,
Chen S.
Beckman Research Institute of the City of Hope, Duarte, California, USA.
Estrogen stimulates the proliferation of breast cancer cells and the growth of estrogen-responsive tumors. The aromatase enzyme, which converts androgen to estrogen, plays a key role in breast carcinogenesis. The pomegranate fruit, a rich source of ellagitannins (ET), has attracted recent attention due to its anticancer and antiatherosclerotic properties. On consumption, pomegranate ETs hydrolyze, releasing ellagic acid, which is then converted to 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one ("urolithin") derivatives by gut microflora. The purpose of this study was to investigate the antiaromatase activity and inhibition of testosterone-induced breast cancer cell proliferation by ET-derived compounds isolated from pomegranates. A panel of 10 ET-derived compounds including ellagic acid, gallagic acid, and urolithins A and B (and their acetylated, methylated, and sulfated analogues prepared in our laboratory) were examined for their ability to inhibit aromatase activity and testosterone-induced breast cancer cell proliferation. Using a microsomal aromatase assay, we screened the panel of ET-derived compounds and identified six with antiaromatase activity. Among these,
urolithin B (UB) was shown to most effectively inhibit aromatase activity in a live cell assay. Kinetic analysis of UB showed mixed inhibition, suggesting more than one inhibitory mechanism. Proliferation assays also determined that UB significantly inhibited testosterone-induced MCF-7aro cell proliferation. The remaining test compounds also exhibited antiproliferative activity, but to a lesser degree than UB. These studies suggest that pomegranate ET-derived compounds have potential for the prevention of estrogen-responsive breast cancers.
PMID: 20051378 [PubMed - indexed for MEDLINE]
Linear Mode
