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http://hdl.handle.net/10553/112325
Título: | JKST6, a novel multikinase modulator of the BCR-ABL1/STAT5 signaling pathway that potentiates direct BCR-ABL1 inhibition and overcomes imatinib resistance in chronic myelogenous leukemia | Autores/as: | Aranda Tavío, Haidée Magdalena Recio Cruz, Carlota Pilar Martín-Acosta, Pedro Guerra Rodríguez, Miguel Alfonso Brito Casillas, Yeray Blanco, Rosa Junco, Vanessa León, Javier Montero, Juan Carlos Gandullo-Sánchez, Lucía McNaughton-Smith, Grant Zapata, Juan Manuel Pandiella, Atanasio Amesty, Angel Estévez-Braun, Ana Fernández Pérez, Leandro Fco Guerra Hernández, Carlos Borja |
Clasificación UNESCO: | 32 Ciencias médicas 3209 Farmacología 320101 Oncología |
Palabras clave: | Chronic myelogenous leukemia BCR-ABL1 Synergism Imatinib resistance |
Fecha de publicación: | 2021 | Proyectos: | Desarrollo Preclínico de Nuevas Estructuras Bioactivas Moduladoras de Las Actividades Oncogénicas de Stat3/5 O de Los Receptores de Estrógenos Cribado Farmacológico de Librerías Químicas y Desarrollo Preclínico de Nuevas Entidades Moduladoras de Los Oncogenes Stat3/5 y Yap1, y Del Receptor de Estrógenos (Serm) Aplicación de Una Plataforma de Bioensayos en El Cribado de Bibliotecas Químicas Inspiradas en la Biodiversidad: Identificación y Desarrollo de Moléculas Con Interés Biomédico en Oncología. |
Publicación seriada: | Biomedicine and Pharmacotherapy | Resumen: | Chronic myelogenous leukemia (CML) is a hematological malignancy that highly depends on the BCR-ABL1/STAT5 signaling pathway for cell survival. First-line treatments for CML consist of tyrosine kinase inhibitors that efficiently target BCR-ABL1 activity. However, drug resistance and intolerance are still therapeutic limitations in Ph+ cells. Therefore, the development of new anti-CML drugs that exhibit alternative mechanisms to overcome these limitations is a desirable goal. In this work, the antitumoral activity of JKST6, a naphthoquinone-pyrone hybrid, was assessed in imatinib-sensitive and imatinib-resistant human CML cells. Live-cell imaging analysis revealed JKST6 potent antiproliferative activity in 2D and 3D CML cultures. JKST6 provoked cell increase in the subG1 phase along with a reduction in the G0/G1 phase and altered the expression of key proteins involved in the control of mitosis and DNA damage. Rapid increases in Annexin V staining and activation/cleavage of caspases 8, 9 and 3 were observed after JKST6 treatment in CML cells. Of interest, JKST6 inhibited BCR-ABL1/STAT5 signaling through oncokinase downregulation that was preceded by rapid polyubiquitination. In addition, JKST6 caused a transient increase in JNK and AKT phosphorylation, whereas the phosphorylation of P38-MAPK and Src was reduced. Combinatory treatment unveiled synergistic effects between imatinib and JKST6. Notably, JKST6 maintained its antitumor efficacy in BCR-ABL1-T315I-positive cells and CML cells that overexpress BCR-ABL and even restored imatinib efficacy after a short exposure time. These findings, together with the observed low toxicity of JKST6, reveal a novel multikinase modulator that might overcome the limitations of BCR-ABL1 inhibitors in CML therapy. | URI: | http://hdl.handle.net/10553/112325 | ISSN: | 0753-3322 | DOI: | 10.1016/j.biopha.2021.112330 | Fuente: | Biomedicine and Pharmacotherapy [ISSN 0753-3322], v. 144, 112330, (Diciembre 2021) |
Colección: | Artículos |
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