Cantharidin Effects on Protein Phosphatases and the Phosphorylation State of Phosphoproteins in Mice

Eldridge, R; Casida, John E.

doi:10.1006/taap.1995.1013

Cited by 36 publications

(11 citation statements)

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“…In our experiments, in which zebrafish embryos were treated with Endothall, the effective dose was close to the toxic dose. This finding is supported by studies of Cantharidin in mice by others (Eldridge and Casida, 1995; Wang, 1989). Nevertheless, there are several lines of evidence that suggest that members of the PPP1 and PPP2 families have specific roles in vascular formation.…”

Section: Discussionsupporting

confidence: 80%

Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Kalén

Wallgard

Asker³

et al. 2009

Chemistry & Biology

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SUMMARY We combined reverse and chemical genetics to identify targets and compounds modulating blood vessel development. Through transcript profiling in mice, we identified 150 potentially druggable microvessel-enriched gene products. Orthologs of 50 of these were knocked down in a reverse genetic screen in zebrafish, demonstrating that 16 were necessary for developmental angiogenesis. In parallel, 1280 pharmacologically active compounds were screened in a human cell-based assay, identifying 28 compounds selectively inhibiting endothelial sprouting. Several links were revealed between the results of the reverse and chemical genetic screens, including the serine/threonine (S/T) phosphatases ppp1ca, ppp1cc, and ppp4c and an inhibitor of this gene family; Endothall. Our results suggest that the combination of reverse and chemical genetic screens, in vertebrates, is an efficient strategy for the identification of drug targets and compounds that modulate complex biological systems, such as angiogenesis.

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Section: Discussionsupporting

confidence: 80%

Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Kalén

Wallgard

Asker³

et al. 2009

Chemistry & Biology

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“…Regarding NMNAT2 negative modulators, cantharidin potently inhibits protein phosphatase 2A (PP2A) activity in brain4950, while wortmannin inhibits phosphatidylinositol 3-kinase (PI3-K). Ziprasidone HCl is an atypical antipsychotic drug that has been used to treat schizophrenia and bipolar disorder51.…”

Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

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“…A key breakthrough in this area came from studies which showed that cantharidin binds with high affinity to a protein (12), which was thereafter identified as a protein phosphatase (13). Subsequent studies revealed that cantharidin functions as an inhibitor of several PPP family serine/threonine protein phosphatases (PPases), acting as a weak inhibitor of calcineurin (PP2B) and a potent inhibitor of three families (PP1, PP2A, and PP5) of structurally related PPases (14 -16).…”

Section: Introductionmentioning

confidence: 99%

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

Bonness

Aragon

Rutland³

et al. 2006

Molecular Cancer Therapeutics

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Cantharidin, a natural vesicant, inhibits the activity of several PPP family phosphatases, displays antitumor activity, and induces apoptosis in many types of tumor cells. However, the molecular mechanisms underlying the antitumor activity of cantharidin are not clear. Here, doseresponse studies confirm a strong correlation between the suppression of phosphatase activity and cell death. Flow cytometry analysis indicates that before apoptosis, cantharidin delays cell cycle progression following DNA replication with no apparent effect on G 1 -S or S-G 2 phase progression. In contrast, studies with double thymidinesynchronized populations of cells indicate that cantharidin can rapidly arrest growth when added during G 2 or early M phase. Immunostaining indicates that cell cycle arrest occurs before the completion of mitosis and is associated with the appearance of aberrant mitotic spindles. Live cell imaging with time-lapse microscopy shows that cantharidin disrupts the metaphase alignment of chromosomes and produces a prolonged mitotic arrest, with the onset of apoptosis occurring before the onset of anaphase. To explore the contribution of individual phosphatases, antisense oligonucleotides and small interfering RNA were developed to suppress the expression of cantharidinsensitive phosphatases. The suppression of PP2AA, but not PP2AB, is sufficient to induce metaphase arrest, during which time lagging chromosomes are observed moving between the spindle poles and the metaphase plate. Immunostaining revealed slightly abnormal, yet predominately bipolar, mitotic spindles. Nonetheless, after a 10-to 15-hour delay, the cells enter anaphase, suggesting that an additional cantharidin-sensitive phosphatase is involved in the progression from metaphase into anaphase or to prevent the onset of apoptosis in cells arrested during mitosis.

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Cantharidin Effects on Protein Phosphatases and the Phosphorylation State of Phosphoproteins in Mice

Cited by 36 publications

References 0 publications

Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Combination of Reverse and Chemical Genetic Screens Reveals Angiogenesis Inhibitors and Targets

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Cantharidin-induced mitotic arrest is associated with the formation of aberrant mitotic spindles and lagging chromosomes resulting, in part, from the suppression of PP2Aα

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