CM363, a novel naphthoquinone derivative which acts as multikinase modulator and overcomes imatinib resistance in chronic myelogenous leukemia.
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.
['Guerra|Borja|B|', 'Martín-Rodríguez|Patricia|P|', 'Díaz-Chico|Juan Carlos|JC|', 'McNaughton-Smith|Grant|G|', 'Jiménez-Alonso|Sandra|S|', 'Hueso-Falcón|Idaira|I|', 'Montero|Juan Carlos|JC|', 'Blanco|Rosa|R|', 'León|Javier|J|', 'Rodríguez-González|Germán|G|', 'Estévez-Braun|Ana|A|', 'Pandiella|Atanasio|A|', 'Díaz-Chico|Bonifacio Nicolás|BN|', 'Fernández-Pérez|Leandro|L|']
D000818:Animals D000970:Antineoplastic Agents D017209:Apoptosis D002453:Cell Cycle D045744:Cell Line, Tumor D049109:Cell Proliferation D002470:Cell Survival D004195:Disease Models, Animal D019008:Drug Resistance, Neoplasm D005260:Female D016044:Fusion Proteins, bcr-abl D006801:Humans D000068877:Imatinib Mesylate D048031:JNK Mitogen-Activated Protein Kinases D020014:K562 Cells D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive D051379:Mice D009285:Naphthoquinones D047428:Protein Kinase Inhibitors D050799:STAT5 Transcription Factor D015398:Signal Transduction D023041:Xenograft Model Antitumor Assays
naphthoquinone imatinib resistance leukemia Bcrl-Abl-Stat5