HCC cell growth is inhibited by demethylcantharidate (0-100 μM; 0, 12, 24, 48, or 72 hours) disodium [1]. Demethylcantharidate (0, 9, 18 or 36 μM; 24 hours) disodium raises Bax/Bcl-2, cleaved caspase-9, and cleaved caspase-3 levels in a dose-dependent manner [1].

The in vivo hepatocellular carcinoma tumorigenesis of SMMC-7721 cells is significantly reduced by demethylcantharidate disodium [1].

Cell Viability Assay[1]
Cell Types: HCC cell lines (SMMC-7721 and Bel-7402)
Tested Concentrations: 0-100 μM
Incubation Duration: 0, 12, 24, 48 or 72 hrs (hours)
Experimental Results: demonstrated anti-proliferative activity in the two HCC cell lines.

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Cell Viability Assay[1]
Cell Types: HCC cells
Tested Concentrations: 0, 9, 18 or 36 µM
Incubation Duration: 24 hrs (hours)
Experimental Results: Induced apoptosis in HCC cells via the intrinsic pathway.

Absorption, Distribution and Excretion
May be absorbed through skin ...
Over 90% of radioactivity from (14)carbon labeled endothall administration orally to rats recovered in feces. Remainder recovered from urine and as expired air. Virtually complete recovery of administered dose within 48 hr.
When bluegills were exposed in aquaria to water containing 2 ppm of (14)Carbon endothall, less than 1% of the herbicide was absorbed by the fish. The concentration of (14)Carbon residues were highest in the viscera and lowest in the flesh. Endothall is also absorbed by the fish when fed through the digestive tract.
...labeled endothall /was administered/ to two lactating rats to determine whether endothall was secreted in milk The animals received a daily oral dose of 0.2 mg endothall (in 10% sucrose solution) for five consecutive days prior to delivery. After birth, dams received a daily dose of 0.4 mg endothall in 10% sucrose solution for five consecutive days. After sacrifice of the pups, no radioactivity was detected in any of the tissues or stomach contents suggesting that endothall was not secreted into the milk of lactating rats.
For more Absorption, Distribution and Excretion (Complete) data for ENDOTHALL (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
The fate of the widely used herbicide, endothall, in various organisms and systems is reviewed. Limited results indicate that endothall absorbed by plants and fish is completely metabolized, but in mammals it is excreted largely as the bound form.

Interactions
The combined preparation of endothall and isopropyl phenylcarbamate, Murbetol, is hundreds of times more herbicidal than either of the ingredients alone.
Cell adhesion and neurite outgrowth, mediated by the neural cell adhesion molecule L1, are inhibited in a dose-dependent manner by ethanol and other small alcohols. Ethanol inhibition of L1-mediated adhesion may contribute to the development of fetal alcohol syndrome. Although the pharmacology of ethanol inhibition of L1 adhesion is well characterized and antagonist molecules have been identified, the cellular mechanism underlying this phenomenon is unclear. The identification of ethanol-sensitive and insensitive cell lines derived from the same stable transfection of L1 suggests that additional cellular factors regulate the ethanol effect. Here we investigate the role of intracellular signaling molecules in ethanol inhibition of L1 adhesion. L1-mediated functions can be controlled by phosphorylation events and several kinases are known to phosphorylate L1, including casein kinase II (CK2), ERK 1/2 and p90rsk. Pharmacological inhibition of CK2 activity blocked ethanol inhibition of L1 adhesion in ethanol-sensitive NIH/3T3 cells stably expressing human L1 (2A2-L1) and in BMP-7 treated NG108 cells. However, ethanol had no direct effect on CK2 activity or subunit localization. We next asked what effect protein phosphatase inhibitors would have on ethanol sensitivity. Pretreating 2A2-L1 cells and BMP-7 treated NG108 cells with okadaic acid significantly reduced ethanol inhibition of L1 adhesion in a dose dependent manner (IC50 = 10 nM). Similar effects were seen with another phosphatase inhibitor, endothall. Neither of these drugs had any effect on L1 adhesion in. the absence of ethanol. The necessity of CK2 and phosphatase activity for ethanol sensitivity may be explained by the fact that phosphatase PP2A is activated by CK2. Thus, inhibiting CK2 could also reduce PP2A activity. The fact that ethanol has no direct effect on CK2 activity supports the idea that another protein (PP2A), besides CK2, may be a more direct regulator of ethanol sensitivity for L1 adhesion. Together, these results show that ethanol' inhibition of L1 adhesion can be controlled by intracellular signaling pathways and suggest new avenues for the development of ethanol antagonists.
The beneficial effect of phosphodiesterase 5A inhibition in ischemia/reperfusion injury and cardiac hypertrophy is well established. Inhibition of the cardiac Na(+)/H(+) exchanger (NHE-1) exerts beneficial effects on these same conditions, and a possible link between these therapeutic strategies was suggested. Experiments were performed in isolated cat cardiomyocytes to gain insight into the intracellular pathway involved in the reduction of NHE-1 activity by phosphodiesterase 5A inhibition. NHE-1 activity was assessed by the rate of intracellular pH recovery from a sustained acidic load in the absence of bicarbonate. Phosphodiesterase 5A inhibition with sildenafil (1 umol/L) did not affect basal intracellular pH; yet, it did decrease proton efflux (J(H); in millimoles per liter per minute) after the acidic load (proton efflux: 6.97 +/- 0.43 in control versus 3.31+/- 0.58 with sildenafil; P<0.05). The blockade of both protein phosphatase 1 and 2A with 100 nmol/L of okadaic acid reverted the sildenafil effect (proton efflux: 6.77+/- 0.82). In contrast, selective inhibition of protein phosphatase 2A (1 nmol/L of okadaic acid or 100 umol/L of endothall) did not (3.86 +/- 1.0 and 2.61+/- 1.2), suggesting that only protein phosphatase 1 was involved in sildenafil-induced NHE-1 inhibition. Moreover, sildenafil prevented the acidosis-induced increase in NHE-1 phosphorylation without affecting activation of the extracellular signal-regulated kinase 1/2-p90(RSK) pathway. Our results suggest that phosphodiesterase 5A inhibition decreases NHE-1 activity, during intracellular pH recovery after an acidic load, by a protein phosphatase 1-dependent reduction in NHE-1 phosphorylation.

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Non-Human Toxicity Values
LD50 Rat oral 38-51 mg/kg for acid (technical)
LD50 Rat oral 182-197 mg/kg /Sodium salt (19.2% solution)/
LD50 Rat oral 206 mg/kg /Amine salt (66.7% formulation)/
LD50 Rat (male) oral 57 mg/kg
For more Non-Human Toxicity Values (Complete) data for ENDOTHALL (6 total), please visit the HSDB record page.

[1]. Sodium demethylcantharidate induces apoptosis in hepatocellular carcinoma cells via ER stress. Am J Transl Res. 2019;11(5):3150-3158. Published 2019 May 15.

The monohydrate is in the form of colorless crystals. Non corrosive. Used as a selective herbicide.
Endothal-disodium is an organic molecular entity.
A preparation of hog pancreatic enzymes standardized for lipase content.
See also: Pancrelipase (annotation moved to); Endothal-disodium (annotation moved to).

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Mechanism of Action
Cyclic AMP-dependent protein kinase (PKA) and Ca(2+)-calmodulin dependent protein kinase II (CaMKII)-mediated phosphorylation activate histamine synthesis in nerve endings, but the phosphatases deactivating it had not been studied. In this work we show that the protein phosphatase 2A (PP2A)/protein phosphatase 1 (PP1) inhibitor okadaic acid increases histamine synthesis up to twofold in rat cortical miniprisms containing histaminergic nerve endings. This effect was mimicked by the PP2A/PP1 inhibitor calyculin, but not by the inactive analog 1-norokadaone. Other phosphatase inhibitors like endothall (PP2A), cypermethrin and cyclosporin A (protein phosphatase 2B, PP2B) had much lower effects. The effects of okadaic acid appeared to be mediated by an activation of the histamine synthesizing enzyme, histidine decarboxylase. PKA-mediated activation of histamine synthesis decreased the EC(50) and maximal effects of okadaic acid. On the other hand, CaMKII-mediated activation of histamine synthesis decreased okadaic acid maximal effects, but it increased its EC(50). In conclusion, our results indicate that brain histamine synthesis is subjected to regulation by phosphatases PP2A and PP1, and perhaps also PP2B as well as by protein kinases.
... Protein phosphatase (PP) inhibitors and rat cerebellar glial cells in primary culture /were used/ to investigate the role of PP activity in the ability of glial cells to detoxify exogenously applied hydrogen peroxide (H2O2). The marine toxin okadaic acid (OKA), a potent PP1 and PP2A inhibitor, caused a concentration-dependent degeneration of astrocytes and increased the formation of hydroperoxide radicals significantly. Subtoxic exposures to OKA significantly potentiated toxicity by exogenous H2O2. The concentration of H2O2 that reduced by 50% the survival of astrocytes after 3 hr was estimated at 720+/-40 uM in the absence and 85+/-30 uM in the presence of the toxin. The PP inhibitors calyculin A and endothall also potentiated H2O2 toxicity in cerebellar astrocytes. OKA caused a time-dependent inhibition of both glial catalase and glutathione peroxidase, reducing by approximately 50% the activity of these enzymes after 3 hr, whereas other enzymatic activities remained unaffected. Also, OKA reduced the cellular content of total glutathione and elevated oxidized glutathione to about 25% of total glutathione. OKA-treated astrocytes cleared H2O2 from the incubation medium approximately two times more slowly than control cultures. Our results suggest a prominent role for PP activity in the antioxidant mechanisms protecting astrocytes against damage by H2O2.

C8H8NA2O5

230.13

230.017

129-67-9

Sodium Demethylcantharidate;13114-29-9

8519

White to off-white solid powder

447.8ºC at 760 mmHg

Converted to anhydride at 90 °C
Colorless crystals. MP: 144 °C /Endothall monohydrate/

190.5ºC

2.88E-09mmHg at 25°C

0

5

0

15

224

0

XRHVZWWRFMCBAZ-UHFFFAOYSA-L

InChI=1S/C8H10O5.2Na/c9-7(10)5-3-1-2-4(13-3)6(5)8(11)12;;/h3-6H,1-2H2,(H,9,10)(H,11,12);;/q;2*+1/p-2

disodium;7-oxabicyclo[2.2.1]heptane-2,3-dicarboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

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

H2O : 33.33 mg/mL (144.83 mM)
DMSO : < 1 mg/mL

Solubility in Formulation 1: 50 mg/mL (217.27 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.

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