Patricia Martín-Rodríguez

A series of 34 1,2,3-triazole-naphthoquinone conjugates were synthesized via copper-catalyzed cycloaddition (CuAAC). They were evaluated for their in vitro antimalarial activity against chloroquine-sensitive strains of Plasmodium falciparum and against three different tumor cell lines (SKBr-3, MCF-7, HEL). The most active antimalarial compounds showed a low antiproliferative activity. Simplified analogues were also obtained and some structure–activity relationships were outlined. The best activity was obtained by compounds 3s and 3j, having IC₅₀ of 0.8 and 1.2 μM, respectively. Molecular dockings were also carried on Plasmodium falciparum enzyme dihydroorotate dehydrogenase (PfDHODH) in order to rationalize the results.

The signal transducer and activator of transcription (STAT) are transcription factors that work via JAK/STAT pathway regulating the expression of genes involved in cell survival, proliferation, differentiation, development, immune response, and, among other essential biological functions, hematopoiesis. JAK/STAT signaling is strictly regulated under normal physiological conditions. However, a large group of diverse diseases has been associated to an aberrant regulation of STAT factors. Erroneous modulation of the pathway leads to constitutive STAT activation, thereby driving proliferation, inflammation, and an uncontrolled immune response. Deregulated STAT5 activation has been found in the development of many hematopoietic tumors, including chronic and acute leukemias, polycythemia vera, and lymphoma. Mutations in the kinases that phosphorylate STAT5, and/or overexpression of the upstream receptor-associated tyrosine kinases have been suggested as the main drivers of constitutive STAT5 activation. Hyper-activated STAT5 leads to the aberrant expression of its target genes including antiapoptotic, proliferative, and pro-inflammatory genes, favouring tumorigenesis. In this review, we intent to discuss the biology of JAK/STAT pathway, with particular focus on STAT5 and its crucial role in the development and progression of hematologic malignancies. Furthermore, we provide a synopsis of potential therapeutic strategies based on STAT5 activity inhibition that may represent an excellent opportunity for drug development in oncohematology.

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 (IC50_AUC = 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.

[This corrects the article DOI: 10.18632/oncotarget.11425.].

Naphthoquinones are among the most active natural products obtained from plants and microorganisms. Naphthoquinones exert their biological activities through pleiotropic mechanisms that include reactivity against cell nucleophiles, generation of reactive oxygen species (ROS) and inhibition of proteins. Here we report a mechanistic antiproliferative study performed in the yeast Saccharomyces cerevisiae for several derivatives of three important natural naphthoquinones: lawsone, juglone and β-lapachone. We have found that (i) the free hydroxyl group of lawsone and juglone modulates toxicity; (ii) lawsone and juglone derivatives differ in their mechanisms of action, being ROS generation more important for the former; and (iii) a subset of derivatives possess the capability to disrupt mitochondrial function, being β-lapachones the most potent compounds in this respect. In addition, we have cross-compared yeast results with antibacterial and antitumor activities. We discuss the relationship between the mechanistic findings, the antiproliferative activities and the physicochemical properties of the naphthoquinones.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Borja Guerra1, 2, 3, *, Patricia Martín-Rodríguez1, *, Juan Carlos Díaz-Chico1, 3, Grant McNaughton-Smith4, Sandra Jiménez-Alonso3, 7, Idaira Hueso-Falcón4, Juan Carlos Montero5, Raquel Blanco6, Javier León6, Germán Rodríguez-González4, Ana Estévez-Braun3, 7, Atanasio Pandiella5, Bonifacio Nicolás Díaz-Chico1, 3, 4, Leandro Fernández-Pérez1, 3 1Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña 2Unidad de Apoyo a la Docencia en Enfermería-Fuerteventura, Universidad de Las Palmas de Gran Canaria, España 3Instituto Canario de Investigación sobre el Cáncer (ICIC), España 4Centro Atlántico del Medicamento (CEAMED), España 5Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, España 6Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), España 7Departamento de Química Orgánica, Instituto de Bio-Orgánica Antonio González (CIBICAN), Universidad de la Laguna, España *These authors contributed equally to this work Correspondence to: Leandro Fernández-Pérez, email: leandrofco.fernandez@ulpgc.es Keywords: leukemia, naphthoquinone, Bcrl-Abl-Stat5, imatinib resistance Received: April 23, 2016 Accepted: July 28, 2016 Published: August 19, 2016