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1.
J Mol Model ; 24(10): 303, 2018 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-30280322

RESUMEN

The serine/threonine protein phosphatase type 5 (PP5) is a promising target for designing new antitumor drugs. This enzyme is a member of the PPP phosphatases gene family, which catalyzes a dephosphorylation reaction: a regulatory process in the signal transduction pathway that controls various biological processes. The aim of this work is to study and compare the inhibition of PP5 by ten cantharidin-like inhibitors in order to bring about contributions relevant to the better comprehension of their inhibitory activity. In this theoretical investigation, we used molecular dynamics techniques to understand the role of key interactions that occur in the protein active site; QM calculations were employed to study the interaction mode of these inhibitors in the enzyme. In addition, atoms in molecules (AIM) calculations were carried out to characterize the chemical bonds among the atoms involved and investigate the orbital interactions with their respective energy values. The obtained results suggest that the Arg275, Asn303, His304, His352, Arg400, His427, Glu428, Val429, Tyr451, and Phe446 residues favorably contribute to the interactions between inhibitors and PP5. However, the Asp271 and Asp244 amino acid residues do not favor such interactions for some inhibitors. Through the QM calculations, we can suggest that the reactional energy of the coordination mechanism of these inhibitors in the PP5 active site is quite important and is responsible for the inhibitory activity. The AIM technique employed in this work was essential to get a better comprehension of the transition states acquired from the mechanism simulation. This work offers insights of how cantharidin-like inhibitors interact with human PP5, potentially allowing the design of more specific and even less cytotoxic drugs for cancer treatments. Graphical Abstract Interactions of cantharidin-like inhibitors with human protein phosphatase-5 in a Mg2+ system.


Asunto(s)
Cantaridina/farmacología , Simulación de Dinámica Molecular , Proteínas Nucleares/antagonistas & inhibidores , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Cantaridina/análogos & derivados , Cantaridina/química , Dominio Catalítico , Cationes Bivalentes/química , Diseño de Fármacos , Inhibidores Enzimáticos/farmacología , Humanos , Magnesio/química , Proteínas Nucleares/química , Fosfoproteínas Fosfatasas/química
2.
Braz J Med Biol Res ; 50(7): e5920, 2017 Jul 03.
Artículo en Inglés | MEDLINE | ID: mdl-28678918

RESUMEN

As an active constituent of the beetle Mylabris used in traditional Chinese medicine, cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays a crucial role in cell cycle progression, apoptosis, and cell fate. The role and possible mechanisms exerted by cantharidin in cell growth and metastasis of breast cancer were investigated in this study. Cantharidin was found to inhibit cell viability and clonogenic potential in a time- and dose-dependent manner. Cell cycle analysis revealed that cell percentage in G2/M phase decreased, whereas cells in S and G1 phases progressively accumulated with the increasing doses of cantharidin treatment. In a xenograft model of breast cancer, cantharidin inhibited tumor growth in a dose-dependent manner. Moreover, high doses of cantharidin treatment inhibited cell migration in wound and healing assay and downregulated protein levels of major matrix metalloproteinases (MMP)-2 and MMP-9. MDA-MB-231 cell migration and invasion were dose-dependently inhibited by cantharidin treatment. Interestingly, the members of the mitogen-activated protein kinase (MAPK) signaling family were less phosphorylated as the cantharidin dose increased. Cantharidin was hypothesized to exert its anticancer effect through the MAPK signaling pathway. The data of this study also highlighted the possibility of using PP2A as a therapeutic target for breast cancer treatment.


Asunto(s)
Antineoplásicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Cantaridina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Ratones
3.
Rev. bras. pesqui. méd. biol ; Braz. j. med. biol. res;50(7): e5920, 2017. graf
Artículo en Inglés | LILACS | ID: biblio-951704

RESUMEN

As an active constituent of the beetle Mylabris used in traditional Chinese medicine, cantharidin is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays a crucial role in cell cycle progression, apoptosis, and cell fate. The role and possible mechanisms exerted by cantharidin in cell growth and metastasis of breast cancer were investigated in this study. Cantharidin was found to inhibit cell viability and clonogenic potential in a time- and dose-dependent manner. Cell cycle analysis revealed that cell percentage in G2/M phase decreased, whereas cells in S and G1 phases progressively accumulated with the increasing doses of cantharidin treatment. In a xenograft model of breast cancer, cantharidin inhibited tumor growth in a dose-dependent manner. Moreover, high doses of cantharidin treatment inhibited cell migration in wound and healing assay and downregulated protein levels of major matrix metalloproteinases (MMP)-2 and MMP-9. MDA-MB-231 cell migration and invasion were dose-dependently inhibited by cantharidin treatment. Interestingly, the members of the mitogen-activated protein kinase (MAPK) signaling family were less phosphorylated as the cantharidin dose increased. Cantharidin was hypothesized to exert its anticancer effect through the MAPK signaling pathway. The data of this study also highlighted the possibility of using PP2A as a therapeutic target for breast cancer treatment.


Asunto(s)
Humanos , Animales , Femenino , Conejos , Neoplasias de la Mama/tratamiento farmacológico , Cantaridina/farmacología , Transducción de Señal/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Antineoplásicos/farmacología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ensayos de Selección de Medicamentos Antitumorales , Movimiento Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos
4.
Genet Mol Res ; 12(4): 4393-404, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-24222219

RESUMEN

The molecular and biochemical effects of an insecticidal toxin extracted from Meloidae beetles were investigated on Helicoverpa armigera. The toxin was identified as cantharidin, a well-known natural compound produced by beetles of family Meloidae and Oedemeridae. Furthermore, the effect of the toxin on the metabolic enzymes alkaline phosphatase (ALP) and glutathione S-transferase (GST), responsible for the metabolism of insecticides, was also investigated. Results of a diet incorporation bioassay performed under laboratory conditions showed that the LC50 value of cantharidin was 0.068 mg/g. The body weight of the insect was also significantly reduced by cantharidin treatment. The LC10 concentration of cantharidin, 0.01 mg/g, was also tested to determine its effect on ALP and GST. Our results showed that cantharidin significantly inhibited ALP activity after 48 h, whereas GST activity was significantly inhibited after 24 h. The decline of ALP and GST transcript levels was also validated by semiquantitative RT-PCR analysis. It may be concluded from the results that ALPs and GSTs may be targets of the cantharidin intoxication mechanism. Moreover, the inability of ALP and GST to metabolize cantharidin shows that the mechanism of detoxification for cantharidin is different from that for conventional insecticides. On the basis of our investigations, the chemical structure of insecticides may be modified using a model structure of cantharidin, to avoid metabolism by metabolic enzymes.


Asunto(s)
Cantaridina/farmacología , Escarabajos/química , Insecticidas/farmacología , Mariposas Nocturnas/efectos de los fármacos , Fosfatasa Alcalina/antagonistas & inhibidores , Fosfatasa Alcalina/química , Fosfatasa Alcalina/genética , Fosfatasa Alcalina/metabolismo , Animales , Cantaridina/química , Clonación Molecular , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Represión Enzimática , Glutatión Transferasa/antagonistas & inhibidores , Glutatión Transferasa/química , Glutatión Transferasa/genética , Glutatión Transferasa/metabolismo , Proteínas de Insectos/antagonistas & inhibidores , Proteínas de Insectos/química , Proteínas de Insectos/genética , Proteínas de Insectos/metabolismo , Insecticidas/química , Larva/efectos de los fármacos , Larva/enzimología , Larva/crecimiento & desarrollo , Dosificación Letal Mediana , Mariposas Nocturnas/enzimología , Mariposas Nocturnas/crecimiento & desarrollo , Análisis de Secuencia de ADN
5.
Chem Biol Drug Des ; 82(5): 477-99, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23809227

RESUMEN

Chemical and pharmacological information on cantharidin-based small molecules was analyzed. The review summarizes new facts about blister beetles' metabolites for the period 2006-2012. General synthetic approaches to cantharidin-based small molecules as well as their chemical transformations and biological activities related to cantharidin, norcantharidin, cantharidimide, and norcantharimide analogs, especially their inhibitory activity of phosphoprotein phosphatases in cancer treatment, were discussed in this mini review, which could help to design new small molecule modulators for other biological models.


Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Cantaridina/análogos & derivados , Cantaridina/farmacología , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/toxicidad , Cantaridina/uso terapéutico , Cantaridina/toxicidad , Supervivencia Celular/efectos de los fármacos , Escarabajos/química , Escarabajos/metabolismo , Activación Enzimática/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Fosfoproteínas Fosfatasas/antagonistas & inhibidores , Fosfoproteínas Fosfatasas/metabolismo
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