Black Salve Alternative Cancer Treatment (1)

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cancer epithelial cells as assessed by caspase-3 activation assay, Annexin V staining assay, or by visual analysis for the apoptotic morphology changes. Sanguinarine-mediated apoptosis was associated with the increase of nitric oxide (NO) formation in prostate cancer cells as assessed by measurements of nitrites with Sievers nitric oxide analyzer as well as flow cytometry analysis using NO fluorescent sensor. Activation of NO synthase (NOS) activity was crucial for sanguinarine-induced cell death because NOS inhibitor L-NMMA efficiently protected cells from apoptosis. Adenovirusmediated transfer of Cox-2 into LNCaP cells inhibited sanguinarine-induced apoptosis and prevented an increase in NO production. Surprisingly, NO donors failed to induce apoptosis in LNCaP cells, suggesting that constitutive NO generation is not sufficient for triggering apoptosis in these cells. Besides NO generation, NOS is also capable of producing superoxide radicals. Sanguinarine-induced production of superoxide radicals, and the addition of MnTBAP, a scavenger of superoxide radicals, efficiently inhibited sanguinarine-mediated apoptosis. These results suggest that Cox-2 expression rescues prostate cancer cells from sanguinarine-induced apoptosis by a mechanism involving inhibition of NOS activity, and that coadministration of Cox-2 inhibitors with sanguinarine may be developed as a strategy for the management of prostate cancer. (Cancer Res 2006; 66(7): 3726-36) Originally published In Press as doi:10.1074/jbc.M501467200 on March 7, 2005 J. Biol. Chem., Vol. 280, Issue 19, 19078-19086, May 13, 2005 The Benzo[c]phenanthridine Alkaloid, Sanguinarine, Is a Selective, Cell-active Inhibitor of Mitogenactivated Protein Kinase Phosphatase-1*Andreas Vogt{ddagger}, Aletheia Tamewitz, John Skoko, Rachel P. Sikorski, Kenneth A. Giuliano§, and John S. Lazo From the Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a dual specificity phosphatase that is overexpressed in many human tumors and can protect cells from apoptosis caused by DNAdamaging agents or cellular stress. Small molecule inhibitors of MKP-1 have not been reported, in part because of the lack of structural guidance for inhibitor design and definitive assays for MKP-1 inhibition in intact cells. Herein we have exploited a high content chemical complementation assay to analyze a diverse collection of pure natural products for cellular MKP-1 inhibition. Using twodimensional Kolmogorov-Smirnov statistics, we identified sanguinarine, a plant alkaloid with known antibiotic and antitumor activity but no primary cellular target, as a potent and selective inhibitor of MKP-1. Sanguinarine inhibited cellular MKP-1 with an IC50 of 10 µM and showed selectivity for MKP- 1 over MKP-3. Sanguinarine also inhibited MKP-1 and the MKP-1 like phosphatase, MKP-L, in vitro with IC50 values of 17.3 and 12.5 µM, respectively, and showed 5–10-fold selectivity for MKP-3 and MKP-1 over VH-1-related phosphatase, Cdc25B2, or protein-tyrosine phosphatase 1B. In a human tumor cell line with high MKP-1 levels, sanguinarine caused enhanced ERK and JNK/SAPK phosphorylation. A close congener of sanguinarine, chelerythrine, also inhibited MKP-1 in vitro and in whole cells, and activated ERK and JNK/SAPK. In contrast, sanguinarine analogs lacking the benzophenanthridine scaffold did not inhibit MKP-1 in vitro or in cells nor did they cause ERK or JNK/SAPK phosphorylation. These data illustrate the utility of a chemical complementation assay linked with multiparameter high content cellular screening. Received for publication, February 8, 2005 * This work was supported by National Institutes of Health Grants CA78039 and CA52995 and the Fiske Drug Discovery Fund. The costs of publication of this article were defrayed in part by the
payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.§ Current address: Cellumen, Inc., 100 Technology Dr., Pittsburgh, PA 15219. {ddagger} To whom correspondence may be addressed: Dept. of Pharmacology, The Hillman Cancer Center G.27a, University of Pittsburgh, Pittsburgh, PA 15213. Tel.: 412-623-1216; Fax: 412-623-1212; E-mail: avogt@pitt.edu. To whom correspondence may be addressed: Dept. of Pharmacology, Biomedical Science Tower E-1340, University of Pittsburgh, Pittsburgh, PA 15261. Tel.: 412-648- 9319; Fax: 412-648-2229; E-mail: lazo@pitt.edu. Modern black salve research study links http://www.cancerx.org/science_of_bloodroot.html All TumorX (black salve product) list of Peer Reviewed Studies on Bloodroot Chaparral Supplies Trusted vendors of Black salve Centre Force Ships internationally-Freedom to Choose Alternative Treatment for Cancer US/Canadian Customers-HerbHealers.com Non-US/Canadian Customers - AlphaOmegaLabs.com. Source Ingredients Bulk Herbs A-F Pound - The Natural Health Alliance --- has graviola and chapparal Bulk organic herbs, spices & essential oils from Mountain Rose Herbs --- has bloodroot and galangal Links Doctors are Dangerous article on Black salve-doctorsaredangerous.com/articles/skincancer.htm Search black salve on Google Natural news dot com Article on Greg Caton kidnapping cancersalves.com “Truth Quest” website coverage of black salve escape the sickness industry words from willow blog on black salve You tube links Greg Catons’ Channel http://www.youtube.com/user/AlphaOmegaLabs Search Black Salve on Youtube Medical plant Bloodroot
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Black Salve Alternative Cancer Treatment (1)

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