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      Combination of α-Tomatine and Curcumin Inhibits Growth and Induces Apoptosis in Human Prostate Cancer Cells

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          Abstract

          α-Tomatine is a glycoalkaloid found in tomatoes and curcumin is a major yellow pigment of turmeric. In the present study, the combined effect of these two compounds on prostate cancer cells was studied. Treatment of different prostate cancer cells with curcumin or α-tomatine alone resulted in growth inhibition and apoptosis in a concentration-dependent manner. Combinations of α-tomatine and curcumin synergistically inhibited the growth and induced apoptosis in prostate cancer PC-3 cells. Effects of the α-tomatine and curcumin combination were associated with synergistic inhibition of NF-κB activity and a potent decrease in the expression of its downstream gene Bcl-2 in the cells. Moreover, strong decreases in the levels of phospho-Akt and phosphor-ERK1/2 were found in PC-3 cells treated with α-tomatine and curcumin in combination. In animal experiment, SCID mice with PC-3 xenograft tumors were treated with α-tomatine and curcumin. Combination of α-tomatine and curcumin more potently inhibited the growth of PC-3 tumors than either agent alone. Results from the present study indicate that α-tomatine in combination with curcumin may be an effective strategy for inhibiting the growth of prostate cancer.

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          Transcriptional regulation of bcl-2 by nuclear factor kappa B and its significance in prostate cancer.

          Hans J. Johnson, S Catz (2001)
          This work presents direct evidence that the bcl-2 gene is transcriptionally regulated by nuclear factor-kappa B (NF-kappa B) and directly links the TNF-alpha/NF-kappa B signaling pathway with Bcl-2 expression and its pro-survival response in human prostate carcinoma cells. DNase I footprinting, gel retardation and supershift analysis identified a NF-kappa B site in the bcl-2 p2 promoter. In the context of a minimal promoter, this bcl-2 p2 site 1 increased transcription 10-fold in the presence of the p50/p65 expression vectors, comparable to the increment observed with the consensus NF-kappa B site, while for the full p2 promoter region transcriptional activity was increased sixfold by over-expression of NF-kappa B, an effect eliminated by mutating the bcl-2 p2 site 1. The expression of Bcl-2 has been linked to the hormone-resistant phenotype of advanced prostate cancer. Here we show that an increase in the level of expression of Bcl-2 in the human prostate carcinoma cell line LNCaP observed in response to hormone withdrawal is further augmented by TNF-alpha treatment, and this effect is abated by inhibitors of NF-kappa B. Concomitantly, bcl-2 p2 promoter studies in LNCaP cells show a 40-fold increase in promoter activity after stimulation with TNF-alpha in the absence of hormone.
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            Evaluation of combination chemotherapy: integration of nonlinear regression, curve shift, isobologram, and combination index analyses.

            M. Guillaume Wientjes, Liang-yu Zhao, Jessie Au (2004)
            Isobologram and combination index (CI) analyses are the two most popular methods for evaluating drug interactions in combination cancer chemotherapy. As the commonly used CI-based software program uses linear regression, our first objective was to evaluate the effects of logarithmic data transformation on data analysis and conclusions. Monte-Carlo simulations were conducted with experimentally relevant parameter values to generate error-containing effect or concentration-effect data of single agents and combinations. The simulated data were then analyzed with linear and nonlinear regression. The results showed that data transformation reduced the accuracy and precision of the regression-derived IC(50), curve shape parameter and CI values. Furthermore, as neither isobologram nor CI analyses provide output of concentration-effect curves for investigator evaluation, our second objective was to develop a method and the associated computer program/algorithm to (a) normalize drug concentrations in IC(50) equivalents and thereby enable simultaneous presentation of the curves for single agents and combinations in a single plot for visual inspection of potential curve shifts, (b) analyze concentration-effect data with nonlinear regression, and (c) use the curve shift analysis simultaneously with isobologram and CI analyses. The applicability of this method was shown with experimentally obtained data for single agent doxorubicin and suramin and their combinations in cultured tumor cells. In summary, this method, by incorporating nonlinear regression and curve shift analysis, although retaining the attractive features of isobologram and CI analyses, reduced the potential errors introduced by logarithmic data transformation, enabled visual inspection of data variability and goodness of fit of regression analysis, and simultaneously provided information on the extent of drug interaction at different combination ratios/concentrations and at different effect levels.
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              Tomato glycoalkaloids: role in the plant and in the diet.

              Mendel Friedman (2002)
              Tomatoes, a major food source for humans, accumulate a variety of secondary metabolites including phenolic compounds, phytoalexins, protease inhibitors, and glycoalkaloids. These metabolites protect against adverse effects of hosts of predators including fungi, bacteria, viruses, and insects. Because glycoalkaloids are reported to be involved in host-plant resistance, on the one hand, and to have a variety of pharmacological and nutritional properties in animals and humans, on the other, a need exists to develop a better understanding of the role of these compounds both in the plant and in the diet. To contribute to this effort, this integrated review presents data on the history, composition, and nutrition of tomatoes, with special focus on the assessment of the chemistry, analysis, composition, nutrition, microbiology, and pharmacology of the tomato glycoalkaloids comprising alpha-tomatine and dehydrotomatine; their content in different parts of the tomato plant, in processed tomato products, and in wild and transgenic tomatoes; their biosynthesis, inheritance, metabolism, and catabolism; plant-microbe relationships with fungi, bacteria, viruses, insects, and worms; interactions with ergosterol and cholesterol; disruption of cell membranes; tomatine-induced tomatinases, pantothenate synthetase, steroid hydroxylases, and cytokines; and inhibition of acetylcholinesterase. Also covered are tomato-human pathogen relationships and tomatine-induced lowering of plasma cholesterol and triglycerides and enhancement of the immune system. Further research needs in each of these areas are suggested. The overlapping aspects are discussed in terms of general concepts for a better understanding of the impact of tomato glycoalkaloids in the plant in general and in food in particular. Such an understanding can lead to the creation of improved tomatoes and to improved practices on the farm and in the consumption of tomatoes.
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                Author and article information

                Contributors
                Hong Wang: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 2 December 2015
                Publication date Collection: 2015
                Volume: 10
                Issue: 12
                Electronic Location Identifier: e0144293
                Affiliations
                [1 ]Allan H. Conney Laboratory for Anticancer Research, Guangdong University of Technology, Guangzhou, P. R. China
                [2 ]Department of Chemical and Environmental Engineering, Wuyi University, Jiangmen City, Guangdong Province, P.R. China
                [3 ]Department of Environmental Engineering, Guangdong Industry Technical College, Guangzhou, P.R. China
                [4 ]Cancer Institute of New Jersey, New Brunswick, New Jersey, United States of America
                Rutgers, the State Univesity of New Jersey, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: XZ SG. Performed the experiments: HH XC DL YH ZD XZ. Analyzed the data: HH XC KZ YL RD SG XZ. Contributed reagents/materials/analysis tools: ZD KZ YL. Wrote the paper: HH XC XZ SG RD.

                Article
                Publisher ID: PONE-D-15-43997
                DOI: 10.1371/journal.pone.0144293
                PMC ID: 4668011
                PubMed ID: 26630272
                SO-VID: 4f6ae1f4-071b-4e3d-8b8f-bfdfabc2ed35
                Copyright statement: Copyright @ 2015
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                Date received : 7 October 2015
                Date accepted : 16 November 2015
                Page count
                Figures: 6, Tables: 1, Pages: 15
                Funding
                Guangdong Province, Leadership grant 2011 ( http://pro.gdstc.gov.cn/egrantweb/), National Natural Science Foundation of China, 81272452, 21102020 and 21272043 ( http://www.nsfc.gov.cn/), National Cancer Institute, P30-CA072720 ( http://www.nih.gov/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Custom metadata
                Data Availability All relevant data are within the paper.

                ScienceOpen disciplines: Uncategorized
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