|Title:||CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia||Authors:||Guerra, Borja
Carlos Diaz-Chico, Juan
Montero, Juan Carlos
|UNESCO Clasification:||320101 Oncología
32 Ciencias médicas
|Issue Date:||2017||Project:||Estudios de Nuevos Moduladores de Las Actividades de Stat y de Los Receptores Para Estrogenos: Potencial Aplicacion Como Antitumorales
"Evaluación Preclinica de Nuevas Estructuras Quimicas Diseñadas Para Inhibir la Ruta Oncogenica Jak-Stat O Como Moduladores Selectivos de Los Receptores Estrógenos"
Desarrollo Preclínico de Nuevas Estructuras Bioactivas Moduladoras de Las Actividades Oncogénicas de Stat3/5 O de Los Receptores de Estrógenos
|Journal:||Oncotarget||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 mu M) 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 gamma H2AX. 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.||URI:||http://hdl.handle.net/10553/36049||ISSN:||1949-2553||DOI:||10.18632/oncotarget.11425||Source:||Oncotarget[ISSN 1949-2553],v. 8 (18), p. 29679-29698|
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