title: CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia.
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.
authors.affiliation: Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña.|Unidad de Apoyo a la Docencia en Enfermería-Fuerteventura, Universidad de Las Palmas de Gran Canaria, España.|Instituto Canario de Investigación sobre el Cáncer (ICIC), España.
authors.forename: Borja
authors.initials: B
authors.lastname: Guerra
authors.affiliation: Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña.
authors.forename: Patricia
authors.initials: P
authors.lastname: Martín-Rodríguez
authors.affiliation: Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña.|Instituto Canario de Investigación sobre el Cáncer (ICIC), España.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Díaz-Chico
authors.affiliation: Centro Atlántico del Medicamento (CEAMED), España.
authors.forename: Grant
authors.initials: G
authors.lastname: McNaughton-Smith
authors.affiliation: Instituto Canario de Investigación sobre el Cáncer (ICIC), España.|Departamento de Química Orgánica, Instituto de Bio-Orgánica Antonio González (CIBICAN), Universidad de la Laguna, España.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jiménez-Alonso
authors.affiliation: Centro Atlántico del Medicamento (CEAMED), España.
authors.forename: Idaira
authors.initials: I
authors.lastname: Hueso-Falcón
authors.affiliation: Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, España.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Montero
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), España.
authors.forename: Rosa
authors.initials: R
authors.lastname: Blanco
authors.affiliation: Instituto de Biomedicina y Biotecnología de Cantabria (IBBTEC), España.
authors.forename: Javier
authors.initials: J
authors.lastname: León
authors.affiliation: Centro Atlántico del Medicamento (CEAMED), España.
authors.forename: Germán
authors.initials: G
authors.lastname: Rodríguez-González
authors.affiliation: Instituto Canario de Investigación sobre el Cáncer (ICIC), España.|Departamento de Química Orgánica, Instituto de Bio-Orgánica Antonio González (CIBICAN), Universidad de la Laguna, España.
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
authors.affiliation: Centro de Investigación del Cáncer, CSIC-Universidad de Salamanca, España.
authors.forename: Atanasio
authors.initials: A
authors.lastname: Pandiella
authors.affiliation: Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña.|Instituto Canario de Investigación sobre el Cáncer (ICIC), España.|Centro Atlántico del Medicamento (CEAMED), España.
authors.forename: Bonifacio Nicolás
authors.initials: BN
authors.lastname: Díaz-Chico
authors.affiliation: Instituto de Investigaciones Biomédicas y Sanitarias (IUIBS)-BioPharm Laboratory-Universidad de Las Palmas de Gran Canaria, Epaña.|Instituto Canario de Investigación sobre el Cáncer (ICIC), España.
authors.forename: Leandro
authors.initials: L
authors.lastname: Fernández-Pérez
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D009285:Naphthoquinones; D047428:Protein Kinase Inhibitors; D050799:STAT5 Transcription Factor; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Bcrl-Abl-Stat5; imatinib resistance; leukemia; naphthoquinone