Please use this identifier to cite or link to this item: http://hdl.handle.net/10553/69815
Title: A novel naphthoquinone-coumarin hybrid that inhibits BCR-ABL1-STAT5 oncogenic pathway and reduces survival in imatinib-resistant chronic myelogenous leukemia cells
Authors: Martín-Rodríguez, Patricia 
Guerra, Borja 
Hueso-Falcón, Idaira
Aranda Tavío, Haidee Magdalena 
Díaz-Chico, Juan 
Quintana, José
Estévez, Francisco 
Díaz-Chico, Bonifacio 
Amesty, Angel
Estévez-Braun, Ana
Fernández-Pérez, Leandro 
UNESCO Clasification: 320101 Oncología
3209 Farmacología
Keywords: Bcr-Abl1
Coumarin
Drug Resistance
Imatinib
Leukemia, et al
Issue Date: 2019
Project: Desarrollo Preclínico de Nuevas Estructuras Bioactivas Moduladoras de Las Actividades Oncogénicas de Stat3/5 O de Los Receptores de Estrógenos 
Desarrollo Preclínico de Nuevas Estructuras Bioactivas Moduladoras de Las Actividades Oncogénicas de Stat3/5 O de Los Receptores de Estrógenos 
Journal: Frontiers in Pharmacology 
Abstract: This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). BCR-ABL1-STAT5 is an oncogenic signaling pathway in human chronic myelogenous leukemia (CML) and it represents a valid target for anti-CML drug design. Resistance to direct BCR-ABL1 inhibitors is a common clinical issue, so STAT5 inhibition has become an interesting alternative target. In this study, the effects of NPQ-C6, a novel naphtoquinone-coumarin conjugate, were evaluated on human CML-derived K562 cells. Live-Cell Imaging analysis revealed that NPQ-C6 inhibited 2D (IC50AUC = 1.4 ± 0.6 μM) growth of CML cells. NPQ-C6 increased sub-G1 and reduced G0/G1 cell cycle phases in a dose- and time-dependent manner. This effect on cell cycle was related to increased levels of apoptotic nuclei, cleavage of caspase-3, -9, and PARP and annexin V-positive cells. NPQ-C6 increased γH2AX, a double-strand DNA break marker. NPQ-C6 showed a wide range of modulatory effects on cell signaling through an early increased phosphorylation of JNK, P38-MAPK and AKT, and decreased phosphorylation of ERK1/2, BCR-ABL1, and STAT5. NPQ-C6 inhibited expression of c-MYC and PYM-1, two target gene products of BCR-ABL1/STAT5 signaling pathway. Cytokine-induced activation of STAT5/STAT3-dependent transcriptional and DNA binding activities were also inhibited by NPQ-C6. Notably, NPQ-C6 maintained its activity on BCR-ABL1/STAT5/c-MYC/PIM-1 oncogenic pathway in imatinib-resistant cells. Molecular modeling suggested BCR-ABL1 and JAK2 proteins as NPQ-C6 targets. In summary, our data show a novel multikinase modulator that might be therapeutically effective in BCR-ABL1-STAT5-related malignancies.
URI: http://hdl.handle.net/10553/69815
ISSN: 1663-9812
DOI: 10.3389/fphar.2018.01546
Source: Frontiers In Pharmacology [ISSN 1663-9812], v. 9, (Enero 2019)
Appears in Collections:Artículos
Thumbnail
Adobe PDF (3,87 MB)
Show full item record

SCOPUSTM   
Citations

4
checked on May 2, 2021

WEB OF SCIENCETM
Citations

4
checked on May 2, 2021

Page view(s)

54
checked on May 3, 2021

Download(s)

26
checked on May 3, 2021

Google ScholarTM

Check

Altmetric


Share



Export metadata



Items in accedaCRIS are protected by copyright, with all rights reserved, unless otherwise indicated.