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.
Highlights
Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of cells of the myelogenous lineage [1]
When the effects of transient exposure to CM363 were analyzed by using the Live-Cell Imaging System (Figure 1G), we observed that 2 h of transient exposure to CM363 (IC50AUC = 1.9 ± 0.5 μM) was enough to cause a cytostatic effect on K562 cells for additional 72 h
These results suggest that CML cells are acutely sensitive to CM363 and that they cannot overcome the inhibitory effects on cell growth caused by a short-transient exposure to this novel NPQ derivative
Summary
Chronic Myelogenous Leukemia (CML) is a hematological stem cell disorder characterized by excessive proliferation of cells of the myelogenous lineage [1]. The molecular consequence of this translocation is the replacement of the first exon of c-Abl with sequences from the Bcr gene resulting in a Bcr-Abl fusion gene whose protein product generates a constitutively activated tyrosine kinase. Bcr-Abl activates intracellular signal transduction pathways that promote proliferation and genetic instability while suppressing apoptosis and weakening cellular adhesion [1]. Activation of Stat by Bcr/ Abl leads to increased expression of genes driving cell cycle progression, promoting survival, and oncogenesis signaling pathways downstream of Bcr-Abl kinase [6]. Deletion of Stat in Bcr-Abl+ cells induces apoptosis, even in Bcr-Abl tyrosine kinase inhibitors (TKI)-resistant cells. Stat is constitutively active in many forms of hematologic cancers [5], and, aside Bcr-Abl, it is a signaling hallmark of CML and its activity is associated with poor prognosis [7]
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