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Title: Novel naphthoquinone-coumarin hybrids as inhibitors of BCR-ABL-STAT5 signaling pathway in chronic myelogenous leukemia
Authors: Martín Rodríguez, Patricia 
Guerra, B. 
Hueso-Falcón, I.
Aranda Tavio, Haidee 
Guerra Rodríguez, Miguel A. 
Díaz Chico, Juan Carlos 
Quintana, José 
Estevez, F. 
Díaz-Chico, J. C. 
Amesty, A.
Estévez-Braun, A.
Fernández Pérez, Leandro Fco 
UNESCO Clasification: 3209 Farmacología
Keywords: Naphthoquinone-coumarin
Issue Date: 2018
Journal: Basic and Clinical Pharmacology and Toxicology 
Conference: 1st Meeting in Translational Pharmacology. 38th Spanish Society of Pharmacology meeting. 9th Spanish Society of Pharmacogenetics and Pharmacogenomics meeting (SEFF/SEF 2018) 
Abstract: NPQ and coumarin represent promising scaffolds in medicinal chemistry for finding novel inhibitors of carcinogenic pathways. This is exemplified by the discovery of NPQ-coumarin hybrids as inhibitors of topoisomerase II [1]. BCR-ABL-STAT5 is an oncogenic signaling pathway in Human Chronic Myelogenous Leukemia (CML) and it represents a valid target for anti-CML drug design [2]. In this study, the effects of a novel naphthoquinone-coumarin conjugate NPQ-C6 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 K562 cells. NPQ-C6 caused a dose- and time-dependent cell cycle arrest which was associated with increased levels of apoptotic markers (apoptotic nuclei, cleavage of caspase-3, -9, PARP and annexin V-positive cells) and increased γH2AX expression protein, a double-strand DNA break marker. NPQ-C6 showed multikinase modulatory effects through an early increased phosphorylation of JNK, P38-MAPK and AKT, and decreased phosphorylation of ERK1/2, BCR-ABL and STAT5 and inhibited expression of oncoprotein c-MYC. Molecular modeling suggested to BCR-ABL and JAK2 proteins as potential targets for NPQ-C6. In summary, NPQ-C6 is a novel multikinase modulator that might be effective on BCR-ABL-STAT5 oncogenic pathway in BCR-ABL-STAT5 related malignancies.
ISSN: 1742-7835
DOI: 10.1111/bcpt.13084
Source: Basic and Clinical Pharmacology and Toxicology [ISSN 1742-7835], v. 123 (S2), p. 26-27, P003
Appears in Collections:Actas de congresos
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