PKC (IC50 = 0.7 μM)

L-1210 cell growth is inhibited by chelerythrine (IC50: 0.53 uM) for 48 hours[1]. Chelerythrine (0–20 μM, 24 hours) can increase autophagy and self-healing in cells while suppressing the viability of A549 and NCI-H1299 cells. Chelerythrine (0–5 μM, 24 or 48 hours) can cause SH-SY5Y cells that overexpress BclXL. Death [3]. In SH-SY5Y cells, chelerythrine (2.5–10 μM, 16) can cause necrosis [4]. Chelidonine (0-100 ng/mL, 24 hours) decreases the production of NO and TNF-α in primary macrophages stimulated by LPS. Cheerythrine (MIC: 0.156 mg/mL) exhibits antibacterial activity against MRSA, extended-spectrum beta-lactamase Staphylococcus aureus (ESBLs-SA), and Gram-positive bacteria.

Renal function can be restored and the renal damage caused by partial uniuretic ureteral obstruction (UUO) in neovascularization can be lessened with erythrine (5 mg/kg, intraperitoneal injection, daily) [2]. Increased nocturnal rate, decreased nitrite and TNF-α levels, as well as anti-inflammatory effects were observed in LPS-induced toxic shock after injections of chelerythrine (1–10 mg/kg, i.p.) and 100 μg/kg LPS (first 24 hours and 1 hour) [5].

The benzophenanthridine alkaloid chelerythrine is a potent, selective antagonist of the Ca++/phospholopid-dependent protein kinase (Protein kinase C: PKC) from the rat brain. Half-maximal inhibition of the kinase occurs at 0.66 microM. Chelerythrine interacted with the catalytic domain of PKC, was a competitive inhibitor with respect to the phosphate acceptor (histone IIIS) (Ki = 0.7 microM) and a non-competitive inhibitor with respect to ATP. This effect was further evidenced by the fact that chelerythrine inhibited native PKC and its catalytic fragment identically and did not affect [3H]- phorbol 12,13 dibutyrate binding to PKC. Chelerythrine selectively inhibited PKC compared to tyrosine protein kinase, cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase. The potent antitumoral activity of celerythrine measured in vitro might be due at least in part to inhibition of PKC and thus suggests that PKC may be a model for rational design of antitumor drugs.[1]

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The identification of small molecule inhibitors of antiapoptotic Bcl-2 family members has opened up new therapeutic opportunities, while the vast diversity of chemical structures and biological activities of natural products are yet to be systematically exploited. Here we report the identification of chelerythrine as an inhibitor of BclXL-Bak Bcl-2 homology 3 (BH3) domain binding through a high throughput screening of 107,423 extracts derived from natural products. Chelerythrine inhibited the BclXL-Bak BH3 peptide binding with IC50 of 1.5 micro m and displaced Bax, a BH3-containing protein, from BclXL. Mammalian cells treated with chelerythrine underwent apoptosis with characteristic features that suggest involvement of the mitochondrial pathway. While staurosporine, H7, etoposide, and chelerythrine released cytochrome c from mitochondria in intact cells, only chelerythrine released cytochrome c from isolated mitochondria. Furthermore BclXL-overexpressing cells that were completely resistant to apoptotic stimuli used in this study remained sensitive to chelerythrine. Although chelerythrine is widely known as a protein kinase C inhibitor, the mechanism by which it mediates apoptosis remain controversial. Our data suggest that chelerythrine triggers apoptosis through a mechanism that involves direct targeting of Bcl-2 family proteins[3].

Western Blot analysis [4]
Cell Types: A549 and NCI-H1299 Cell
Tested Concentrations: 10, 15, 20 μM
Incubation Duration: 24 h
Experimental Results: The expression of LC3-II was induced in a beclin 1-dependent manner.

Animal/Disease Models: Unilateral ureteral obstruction (UUO)-induced neonatal rats [2]
Doses: 5 mg/kg
Route of Administration: intraperitoneal (ip) injection, daily
Experimental Results: diminished renal damage (increased kidney weight and restored renal function). Inhibits UUO-induced upregulation of renal injury molecule 1 expression, cell apoptosis and renal fibrosis.

Toxicity Summary
Chelerythrine is a potent, selective, and cell-permeable protein kinase C (PKC) inhibitor. It is also the major active natural product found in the plant Zanthoxylum clava-herculis, exhibiting anti-bacterial activity against Staphylococcus aureus. (Wikipedia) Chelerythrine is a selective inhibitor of group A and B PKC isoforms with an antitumor activity. Inhibition of PKC with chelerythrine chloride induces apoptosis by activation of a neutral sphingomyelinase, accumulation of ceramide, and depletion of sphingomyelin. Chelerythrine is at least 100-fold more selective for PKCs than for other kinases. Chelerythrine competes for the conserved catalytic sites of PKC and seems to be a potent and specific inhibitor of the group A and group B kinases. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. Radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro. Chelerythrine treatment of nude mice bearing SQ-20B HNSCC cells is associated with significant tumor growth delay. Also, treatment with chelerythrine resulted in minimal toxicity. (A15441)

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Toxicity Summary
Chelerythrine is a potent, selective, and cell-permeable protein kinase C (PKC) inhibitor. It is also the major active natural product found in the plant Zanthoxylum clava-herculis, exhibiting anti-bacterial activity against Staphylococcus aureus. (Wikipedia) Chelerythrine is a selective inhibitor of group A and B PKC isoforms with an antitumor activity. Inhibition of PKC with chelerythrine chloride induces apoptosis by activation of a neutral sphingomyelinase, accumulation of ceramide, and depletion of sphingomyelin. Chelerythrine is at least 100-fold more selective for PKCs than for other kinases. Chelerythrine competes for the conserved catalytic sites of PKC and seems to be a potent and specific inhibitor of the group A and group B kinases. Chelerythrine exhibited cytotoxic activity against nine human tumor cell lines tested in vitro. Radioresistant and chemoresistant squamous cell carcinoma lines (HNSCC) undergo apoptosis rapidly after treatment with chelerythrine in vitro. Chelerythrine treatment of nude mice bearing SQ-20B HNSCC cells is associated with significant tumor growth delay. Also, treatment with chelerythrine resulted in minimal toxicity.

[1]. Chelerythrine is a potent and specific inhibitor of protein kinase C. Biochem Biophys Res Commun. 1990 Nov 15;172(3):993-9.

[2]. Protein kinase C inhibitor chelerythrine attenuates partial unilateral ureteral obstruction induced kidney injury in neonatal rats. Life Sci. 2019 Jan 1;216:85-91.

[3]. Identification of chelerythrine as an inhibitor of BclXL function.J Biol Chem. 2003 Jun 6;278(23):20453-6.

[4]. Induction of reactive oxygen species-stimulated distinctive autophagy by chelerythrine in non-small cell lung cancer cells.Redox Biol. 2017 Aug;12:367-376.

[5]. Effect of chelerythrine against endotoxic shock in mice and its modulation of inflammatory mediators in peritoneal macrophages through the modulation of mitogen-activated protein kinase (MAPK) pathway. Inflammation. 2012 Dec;35(6):1814-24.

[6]. Antibacterial mechanism of chelerythrine isolated from root of Toddalia asiatica (Linn) Lam. BMC Complement Altern Med. 2018 Sep 26;18(1):261.

Chelerythrine is a benzophenanthridine alkaloid isolated from the root of Zanthoxylum simulans, Chelidonium majus L., and other Papaveraceae. It has a role as an EC 2.7.11.13 (protein kinase C) inhibitor, an antibacterial agent and an antineoplastic agent. It is a benzophenanthridine alkaloid and an organic cation.
A benzophenanthridine alkaloid evaluated as a kinase-inhibitor.
Chelerythrine has been reported in Corydalis ternata, Zanthoxylum simulans, and other organisms with data available.
Chelerythrine is a benzophenanthridine alkaloid extracted from the plant Greater celandine (Chelidonium majus). It is a potent, selective, and cell-permeable protein kinase C inhibitor.
See also: Sanguinaria canadensis root (part of); Chelidonium majus flowering top (part of).

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The present study aimed to evaluate the renoprotective effects of chelerythrine (CHE), a protein kinase C inhibitor, on neonatal rats after partial unilateral ureteral obstruction (UUO) surgery. New born Sprague Dawley rats were subjected to partial UUO 48 h after birth and received a daily intraperitoneal injection of 5 mg/kg CHE. At 21-day age, the rats were scarified and the kidneys were collected for analysis. Results showed that CHE treatment significantly increased kidney weight and restored renal function in the obstructed kidney. Histological examination demonstrated that CHE attenuated renal injury by reducing renal parenchymal loss and preventing glomerular and tubular degeneration. In addition, CHE inhibited partial UUO-induced upregulated kidney injury molecule-1 expression and apoptosis and renal fibrosis. Moreover, as a PKC inhibitor, CHE significantly inhibited PKCα and PKCβ membrane translocation. This action may be associated with its effects of anti-apoptosis and anti-fibrosis and contribute to the renoprotection. This short-term study suggests that CHE is beneficial for obstructive nephropathy in neonatal rats and provides foundation for further studies to reveal the long-term effects of CHE on obstructive nephropathy in children and infants.[2]

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Chelerythrine (CHE), a natural benzo[c]phenanthridine alkaloid, shows anti-cancer effect through a number of mechanisms. Herein, the effect and mechanism of the CHE-induced autophagy, a type II programmed cell death, in non-small cell lung cancer (NSCLC) cells were studied for the first time. CHE induced cell viability decrease, colony formation inhibition, and apoptosis in a concentration-dependent manner in NSCLC A549 and NCI-H1299 cells. In addition, CHE triggered the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3-II). The CHE-induced expression of LC3-II was further increased in the combination treatment with chloroquine (CQ), an autophagy inhibitor, and large amounts of red-puncta were observed in the CHE-treated A549 cells with stable expression of mRFP-EGFP-LC3, indicating that CHE induces autophagy flux. Silence of beclin 1 reversed the CHE-induced expression of LC3-II. Inhibition of autophagy remarkably reversed the CHE-induced cell viability decrease and apoptosis in NCI-H1299 cells but not in A549 cells. Furthermore, CHE triggered reactive oxygen species (ROS) generation in both cell lines. A decreased level of ROS through pretreatment with N-acetyl-L-cysteine reversed the CHE-induced cell viability decrease, apoptosis, and autophagy. Taken together, CHE induced distinctive autophagy in A549 (accompanied autophagy) and NCI-H1299 (pro-death autophagy) cells and a decreased level of ROS reversed the effect of CHE in NSCLC cells in terms of cell viability, apoptosis, and autophagy.[4]

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A quaternary benzo [c] alkaloid chelerythrine (CHE), which is a traditional herbal prescription, has been used for the treatment of various inflammatory diseases. To gain insight into the anti-inflammatory effect and molecular mechanisms underlying the anti-inflammatory activity of CHE, we used experimentally induced mice endotoxic shock moled and lipopolysaccharide (LPS)-induced murine peritoneal macrophages to examine the anti-inflammatory function of CHE. CHE displayed significant anti-inflammatory effects in experimentally induced mice endotoxic shock model in vivo through inhibition of LPS-induced tumor necrosis factor-alpha (TNF-α) level and nitric oxide (NO) production in serum. Additionally, our data suggest that CHE treatment inhibits LPS-induced TNF-α level and NO production in LPS-induced murine peritoneal macrophages through selective inhibition of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) activation. Moreover, the effects of CHE on NO and cytokine TNF-α production can possibly be explained by the role of p38 MAPK and ERK1/2 in the regulation of inflammatory mediators expression.[5]

C21H18NO4

348.3719

348.123

C, 72.40; H, 5.21; N, 4.02; O, 18.37

34316-15-9

Chelerythrine chloride;3895-92-9; 478-03-5 (OH-); 3895-92-9 (chloride); 34316-15-9

2703

Typically exists as solid at room temperature

195-205ºC

0.72

0

4

2

26

516

0

O1C([H])([H])OC2=C1C([H])=C1C(=C2[H])C([H])=C([H])C2=C3C([H])=C([H])C(=C(C3=C([H])[N+](C([H])([H])[H])=C21)OC([H])([H])[H])OC([H])([H])[H]

LLEJIEBFSOEYIV-UHFFFAOYSA-N

InChI=1S/C21H18NO4/c1-22-10-16-13(6-7-17(23-2)21(16)24-3)14-5-4-12-8-18-19(26-11-25-18)9-15(12)20(14)22/h4-10H,11H2,1-3H3/q+1

1,2-dimethoxy-12-methyl-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium

Toddalin; cheleritrine; Toddaline; broussonpapyrine; [1,3]Benzodioxolo[5,6-c]phenanthridinium, 1,2-dimethoxy-12-methyl-; EINECS 251-930-0; Chelerythrine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)