Oncotarget

Research Papers:

This article has been corrected. Correction in: Oncotarget. 2018; 9:32272.

CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia

Borja Guerra, Patricia Martín-Rodríguez, Juan Carlos Díaz-Chico, Grant McNaughton-Smith, Sandra Jiménez-Alonso, Idaira Hueso-Falcón, Juan Carlos Montero, Rosa Blanco, Javier León, Germán Rodríguez-González, Ana Estévez-Braun, Atanasio Pandiella, Bonifacio Nicolás Díaz-Chico and Leandro Fernández-Pérez _

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Oncotarget. 2017; 8:29679-29698. https://doi.org/10.18632/oncotarget.11425

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Abstract

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, Rosa 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 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, España

4Centro Atlántico del Medicamento, España

5Centro de Investigación del Cáncer, CSIC, Universidad de Salamanca, España

6Instituto de Biomedicina y Biotecnología de Cantabria, CSIC-Universidad de Cantabria, España

7Departamento de Química Orgánica, Instituto de Bio-Orgánica Antonio González, 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

ABSTRACT

Human Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder which is associated with activation of Bcr-Abl-Stat5 oncogenic pathway. Direct Bcr-Abl inhibitors are initially successful for the treatment of CML but over time many patients develop drug resistance. In the present study, the effects of CM363, a novel naphthoquinone (NPQ) derivative, were evaluated on human CML-derived K562 cells. CM363 revealed an effective cell growth inhibition (IC50 = 0.7 ± 0.5 μM) by inducing cancer cells to undergo cell cycle arrest and apoptosis. CM363 caused a dose- and time-dependent reduction of cells in G0/G1 and G2/M phases. This cell cycle arrest was associated with increased levels of cyclin E, pChk1 and pChk2 whereas CM363 downregulated cyclin B, cyclin D3, p27, pRB, Wee1, and BUBR1. CM363 increased the double-strand DNA break marker γH2AX. CM363 caused a time-dependent increase of annexin V-positive cells, DNA fragmentation and increased number of apoptotic nuclei. CM363 triggered the mitochondrial apoptotic pathway as reflected by a release of cytochrome C from mitochondria and induction of the cleavage of caspase-3 and -9, and PARP. CM363 showed multikinase modulatory effects through an early increased JNK phosphorylation followed by inhibition of pY-Bcrl-Abl and pY-Stat5. CM363 worked synergistically with imatinib to inhibit cell viability and maintained its activity in imatinib-resistant cells. Finally, CM363 (10 mg/Kg) suppressed the growth of K562 xenograft tumors in athymic mice. In summary, CM363 is a novel multikinase modulator that offers advantages to circumvent imanitib resistance and might be therapeutically effective in Bcrl-Abl-Stat5 related malignancies.


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