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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 Aguiar, José Martín 
Estévez, Francisco 
Díaz-Chico, Bonifacio 
Amesty, Angel
Estévez-Braun, Ana
Fernández-Pérez, Leandro 
UNESCO Clasification: 320101 Oncología
3209 Farmacología
Keywords: Bcr-Abl1
Drug Resistance
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.
ISSN: 1663-9812
DOI: 10.3389/fphar.2018.01546
Source: Frontiers In Pharmacology [ISSN 1663-9812], v. 9, (Enero 2019)
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