Sanguinarine chloride

1 Corydalis sp. 2 Eschscholzia sp. 3 Sanguinaria sp.

Sanguinarine chloride is a potent and specific inhibitor of PP2C with Ki value of 0.68 μM, and is also a selective and cell-active inhibitor of MKP-1 with IC50 value of 10 μM. Sanguinarine is also an allosteric activator of AMPK [1][2][3].

Protein phosphatase 2C (PP2C) is a serine/threonine-specific phosphatase, the activity of which is dependent on Mg2+ or Mn2+. PP2C dephosphorylates a number of substrates such as cyclin-dependent kinase, mitogen-activated kinase (MAPK) and Bad. Mitogen-activated protein kinase phosphatase-1 (MKP-1) is a dual specificity phosphatase. AMP-activated protein kinase (AMPK) plays an important role in the regulation of cellular metabolism [1][2][3].

Sanguinarine chloride is an inhibitor of PP2C and MKP-1, and also an allosteric activator of AMPK with antibiotic and antitumor activity. Sanguinarine competed with α-casein to inhibit PP2C and exhibited selectivity for PP2C as compared with PP1, PP2A and PP2B. In human promyelocytic leukemia cell line HL60, sanguinarine exhibited cytotoxicity with IC50 value of 0.37 μM and induced apoptosis via a caspase-3/7-dependent mechanism involving the phosphorylation of p38, a PP2C substrate [1]. Sanguinarine inhibited MKP-1 and MKP-L with IC50 values of 17.3 and 12.5 μ
M. In PANC-1 human pancreatic cancer cells, sanguinarine increased ERK and JNK/SAPK phosphorylation [2]. In the MDA MB-231 cell line, sanguinarine caused AMPK and the downstream acetyl-CoA carboxylase (ACC) phosphorylation [3]. In LNCaP and DU145 cells, sanguinarine inhibited cell growth, induced G0/G1 phase arrest and apoptosis [4].

References:
[1].  Aburai N, Yoshida M, Ohnishi M, et al. Sanguinarine as a potent and specific inhibitor of protein phosphatase 2C in vitro and induces apoptosis via phosphorylation of p38 in HL60 cells. Biosci Biotechnol Biochem, 2010, 74(3): 548-552.
[2].  Vogt A, Tamewitz A, Skoko J, et al. The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1. J Biol Chem, 2005, 280(19): 19078-19086.
[3].  Choi J, He N, Sung MK, et al. Sanguinarine is an allosteric activator of AMP-activated protein kinase. Biochem Biophys Res Commun, 2011, 413(2): 259-263.
[4].  Adhami VM, Aziz MH, Reagan-Shaw SR, et al. Sanguinarine causes cell cycle blockade and apoptosis of human prostate carcinoma cells via modulation of cyclin kinase inhibitor-cyclin-cyclin-dependent kinase machinery. Mol Cancer Ther, 2004, 3(8): 933-940.

Cytotoxicity of sanguinarine chloride to cultured human cells from oral tissue.[Pubmed:8829200]

Pharmacol Toxicol. 1996 Jun;78(6):397-403.

The in vitro cytotoxicity of Sanguinarine chloride, a dental product used in the treatment of gingivitis and plaque, was compared using cell lines and primary cells from oral human tissues. For the established cell lines, Sanguinarine chloride exhibited similar potencies to S-G gingival epithelial cells and to KB carcinoma cells, whereas HGF-1 gingival fibroblasts were more tolerant. However, a gingival primary cell culture was more sensitive to Sanguinarine chloride than were the established cell lines. Detailed studies were performed with the S-G cells. The 24-hr midpoint (NR50) cytotoxicity value towards the S-G cells was 7.6 microM, based on the neutral red cytotoxicity assay; vacuolization and multinucleation were noted. When exposed to Sanguinarine chloride for 3 days, a lag in growth kinetics was first observed at 1.7 microM. Damage to the integrity of the plasma membrane was evident, as leakage of lactic acid dehydrogenase occurred during a 3 hr exposure to Sanguinarine chloride at 0.1275 mM and greater. The cytotoxicity of Sanguinarine chloride to the S-G cells was lessened in the presence of an S9 hepatic microsomal fraction from Aroclor-induced rats or by including fetal bovine serum (15%) in the exposure medium. Progressively increasing the pH from 6.0 to 7.8 enhanced the potency of Sanguinarine chloride, presumably due to the enhanced uptake of the lipophilic alkanolamine form, as compared to that of the cationic iminium form.

Sanguinarine as a potent and specific inhibitor of protein phosphatase 2C in vitro and induces apoptosis via phosphorylation of p38 in HL60 cells.[Pubmed:20208361]

Biosci Biotechnol Biochem. 2010;74(3):548-52.

Sanguinarine, a plant alkaloid, was identified as a potent and specific protein phosphatase (PP) 2C inhibitor. It inhibited PP2C competitively with respect to alpha-casein (Ki=0.68 microM) and showed selectivity for PP2C as compared with PP1, PP2A, and PP2B in vitro. In vivo, sanguinarine showed cytotoxicity toward human promyelocytic leukemia cell line HL60, with an IC(50) value of 0.37 microM, and induced apoptosis through a caspase-3/7-dependent mechanism involving the phosphorylation of p38, a PP2Calpha substrate. The apoptosis activity induced by sanguinarine was partially inhibited by a p38 inhibitor, SB203580, and was involved in the phospho-p38 protein in HL60 cells.

The benzo[c]phenanthridine alkaloid, sanguinarine, is a selective, cell-active inhibitor of mitogen-activated protein kinase phosphatase-1.[Pubmed:15753082]

J Biol Chem. 2005 May 13;280(19):19078-86.

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 DNA-damaging 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 two-dimensional 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 microM 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 microM, 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.

Sanguinarine chloride, a benzophenanthridine alkaloid derived from the root of Sanguinaria Canadensis, can stimulate apoptosis via activating the production of reactive oxygen species (ROS). Sanguinarine-induced apoptosis is associated with the activation of JNK and NF-κB.

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