VRCTC-310 — A novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Newman, Robert A.; Vidal, Juan C.; Viskatis, Luis J.; Johnson, Jill; Etcheverry, Martin A.

doi:10.1007/bf00874149

Cited by 50 publications

(34 citation statements)

References 28 publications

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“…Antitumor efficacy in vivo, using a daily im administration of CrTX, has been demonstrated on Lewis lung carcinoma (83% growth inhibition) and MX-1 human mammary carcinoma (69% growth inhibition). A lower activity (44% growth inhibition) was observed with HL-60 leukemia cells, suggesting that CrTX may have a certain specificity toward solid tumors [30] .…”

Section: Discussionmentioning

confidence: 94%

Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

Yan

Yang

Qin

et al. 2007

Acta Pharmacologica Sinica

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Aim: To investigate the role of crotoxin (CrTX)‐induced autophagy in the death of MCF‐7 cells, a caspase‐3‐deficient, human breast cancer cell line. Methods: Cultured MCF‐7 cells were treated with various doses of CrTX, a phospholipase A2 (PLA2) isolated from the venom of the South American rattlesnake, Crotalus durissus terrificus. The cytotoxicity of CrTX in the presence and absence of caspase inhibitors was measured with methyl thiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) leakage assays. The activation of autophagy was determined with transmission electron microscope and monodansylcadaverin (MDC) labeling. The upregulation of lysosomal enzymes, the release of cyto‐chrome c (cyto‐c), and the nuclear translocation of the apoptosis inducing factor (AIF) were examined by immunoblotting and immunofluorescence. Results: CrTX inhibited the viability of MCF‐7 cells in a dose‐ and time‐dependent manner. CrTX‐activated autophagy was revealed by punctuate MDC labeling, and an increase in the formation of autophagosomes as well as apoptosis, as evidenced by nuclear condensation and fragmentation. The activation of cathepsin B, D, and L, in addition to the release of cytochrome c and the relocation of AIF into nuclei, were observed after CrTX treatment. Autophagy inhibitors 3‐methyladenine (3‐MA), NH4Cl, and the pan‐caspase inhibitor, Z‐Val‐Ala‐Asp‐fluoromethylketone (Z‐Vad‐fmk), attenuated CrTX‐induced cell death. Conclusion: An autophagic mechanism contributes to the apoptosis of MCF‐7 cells induced by CrTX.

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Section: Discussionmentioning

confidence: 94%

Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

Yan

Yang

Qin

et al. 2007

Acta Pharmacologica Sinica

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“…Current drugs cannot meet the therapeutic needs [6] . Previous study demonstrated that CrTX has cytotoxic effects on A549 cells, which are human lung adenocarcinoma cells with the wild type p53 gene, and shows synergistic effects when combined with Iressa, which is currently a widely-used drug for lung cancer therapy [7,8] .…”

Section: Introductionmentioning

confidence: 99%

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

et al. 2011

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Aim: To assess the cytotoxic effect of crotoxin (CrTX), a potent neurotoxin extracted from the venom of the pit viper Crotalus durissus terrificus, in human lung adenocarcinoma A549 cells and investigated the underlying mechanisms. Methods: A549 cells were treated with gradient concentrations of CrTX, and the cell cycle and apoptosis were analyzed using a flow cytometric assay. The changes of cellular effectors p53, caspase-3 and cleaved caspase-3, total P38MAPK and pP38MAPK were investigated using Western blot assays. A549 xenograft model was used to examine the inhibition of CrTX on tumor growth in vivo. Results: Treatment of A549 cells with CrTX (25-200 μg/mL) for 48 h significantly inhibited the cell growth in a dose-dependent manner (IC 50 =78 μg/mL). Treatment with CrTX (25 μg/mL) for 24 h caused G1 arrest and induced cell apoptosis. CrTX (25 μg/mL) significantly increased the expression of wt p53, cleaved caspase-3 and phospho-P38MAPK. Pretreatment with the specific P38MAPK inhibitor SB203580 (5 μmol/L) significantly reduced CrTX-induced apoptosis and cleaved caspase-3 level, but G 1 arrest remained unchanged and highly expressed p53 sustained. Intraperitoneal injection of CrTX (10 μg/kg, twice a week for 4 weeks) significantly inhibited A549 tumor xenograft growth, and decreased MVD and VEGF levels. Conclusion: CrTX produced significant anti-tumor effects by inducing cell apoptosis probably due to activation of P38MAPK and caspase-3, and by cell cycle arrest mediated by increased wt p53 expression. In addition, CrTX displayed anti-angiogenic effects in vivo.

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“…Además de su citotoxicidad, el efecto anticancerígeno de estas toxinas podría estar relacionado con autofagia de las células tumorales (40). La escasa toxicidad y la ausencia de neurotoxicidad residual de la crotoxina B en estudios con animales, refuerzan su uso en seres humanos como ya ha sido previamente demostrado (35,36,41).…”

Section: Identificación De Proteínasunclassified

Efecto citotóxico de fosfolipasas A2 del veneno de Crotalus durissus cumanensis de Colombia

Quintana-Castillo¹,

Ávila-Gómez²,

Ceballos-Ruiz³

et al. 2017

Revista Investig. Salud Univ. Boyacá

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RESUMENIntroducción. Los venenos de serpientes representan una fuente importante de proteínas y péptidos, los cuales exhiben diversas actividades biológicas, tales como antibacterianas, antiparasitarias, antivirales, antitumorales, antifúngicas y contra la agregación plaquetaria, entre otras.Las fosfolipasas A2 presentes en los venenos de serpientes son las proteínas más estudiadas en estos modelos. Se ha demostrado que las fosfolipasas A2, activas e inactivas, poseen actividad catalítica contra células tumorales.Objetivo. Aislar, purificar y caracterizar la fosfolipasa A2 del veneno de Crotalus durissus cumanensis para evaluar su actividad antitumoral in vitro.Materiales y métodos. El aislamiento, la purificación y la identificación de la crotoxina B se hizo mediante la cromatografía de exclusión molecular, la cromatografía líquida de alto rendimiento de fase inversa (Reversed Phase High-Performance Liquid Chromatography, RP-HPLC) y la espectrometría de masas. El efecto citotóxico sobre células tumorales (K562) y células normales (células mononucleares de sangre periférica) se determinó utilizando la técnica de MTT.Resultados. La separación y posterior identificación de la crotoxina B del veneno de C. d. cumanensis de Colombia, permitieron evidenciar que esta fosfolipasa A2 posee efecto citotóxico sobre las células mononucleares de sangre periférica con una dosis de 18,23 ± 0,57 µg/ml, mientras que, para las células K562, fue de 2,34 ± 0,199 µg/ml.Conclusiones. Los resultados sugieren la posibilidad de utilizar la crotoxina B aislada del veneno de C.d. cumanensis como un posible recurso terapéutico para su aplicación en humanos.

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VRCTC-310 — A novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Cited by 50 publications

References 28 publications

Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

Autophagy is involved in cytotoxic effects of crotoxin in human breast cancer cell line MCF-7 cells

Anti-tumor activity of CrTX in human lung adenocarcinoma cell line A549

Efecto citotóxico de fosfolipasas A2 del veneno de Crotalus durissus cumanensis de Colombia

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