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1دورية أكاديمية
المؤلفون: Castillo, Ana F., Orlando, Ulises D., Maloberti, Paula M, Prada, Jesica G., Dattilo, Melina A., Solano, Ángela R., Bigi, María M., Ríos Medrano, Mayra A., Torres, María T., Indo, Sebastián, Caroca, Graciela, Contreras, Héctor R, Marelli, Belkis E., Salinas, Facundo J., Salvetti, Natalia R., Ortega, Hugo H., Lorenzano Menna, Pablo, Szajnman, Sergio, Gómez, Daniel E., Rodríguez, Juan B., Podesta, Ernesto J.
المصدر: Cellular and Molecular Life Sciences
مصطلحات موضوعية: Triple negative breast cancer, Castration resistant prostate cancer, Anti-hormone treatment resistance, Chemotherapy resistance
الوصف: National Scientific and Technical Research Council (CONICET) - Argentina, P. U.E 22920160100062 University of Buenos Aires UBACYT 2017-2019 20020160100099BA UBACYT 2018-2019 20020170200347BA National Agency for Scientific and Technological Promotion, MinCyT -Argentina PICT 2016-0418 PICT 2015-3561 PICT 2014-0972
وصف الملف: application/pdf
العلاقة: Cellular and Molecular Life Sciences Volumen: 78 Número: 6 Páginas: 2893-2910 Oct 2020; https://repositorio.uchile.cl/handle/2250/179153Test
الإتاحة: https://doi.org/10.1007/s00018-020-03679-5Test
https://repositorio.uchile.cl/handle/2250/179153Test -
2دورية أكاديمية
المؤلفون: Castillo, Ana F., Orlando, Ulises D., Maloberti, Paula M., Prada, Jesica G., Dattilo, Melina A., Solano, Angela R., Bigi, María M., Ríos Medrano, Mayra A., Torres, María T., Indo, Sebastián, Caroca, Graciela, Contreras, Hector R., Marelli, Belkis E., Salinas, Facundo J., Salvetti, Natalia R., Ortega, Hugo H., Lorenzano Menna, Pablo, Szajnman, Sergio, Gomez, Daniel E., Rodríguez, Juan B.
المصدر: Cellular & Molecular Life Sciences; Mar2021, Vol. 78 Issue 6, p2893-2910, 18p
مصطلحات موضوعية: TUMOR growth, PROSTATE tumors, BREAST tumors, NUCLEAR magnetic resonance spectroscopy, ACYL coenzyme A, EXOCRINE glands
مستخلص: Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis. [ABSTRACT FROM AUTHOR]
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