Abstract
Small molecular inhibitors or drugs targeting specific molecular alterations are widely used in clinic cancer therapy. Despite the success of targeted therapy, the development of drug resistance remains a challenging problem. Identifying drug resistance mechanisms for targeted therapy is an area of intense investigation, and recent evidence indicates that cellular polyploidy may be involved. Here, we demonstrate that the cell cycle kinase inhibitor, Oxindole-1 (Ox-1), induces mitotic slippage, causing resistant polyploidy in acute myeloid leukemia (AML) cells. Indeed, Ox-1 decreases the kinase activity of CDK1 (CDC2)/cyclin B1, leading to inhibition of Bcl-xL phosphorylation and subsequent resistance to apoptosis. Addition of ABT-263, a Bcl-2 family inhibitor, to Ox-1, or the other polyploidy-inducer, ZM447439 (ZM), produces a synergistic loss of cell viability with greater sustained tumor growth inhibition in AML cell lines and primary AML blasts. Furthermore, genetic knockdown of Bcl-xL, but not Bcl-2, exhibited synergistic inhibition of cell growth in combination with Ox-1 or ZM. These data demonstrate that Bcl-xL is a key factor in polyploidization resistance in AML, and that suppression of Bcl-xL by ABT-263, or siRNAs, may hold therapeutic utility in drug-resistant polyploid AML cells.
Highlights
Genomic instability, a hallmark of transformed cells, is thought to drive tumorigenesis by favoring the generation of aggressive tumor cells with a reduced propensity for apoptosis [1]
Alteration in the activity and expression of proteins have already been linked to the onset of resistance [34], but recent evidence indicates that polyploidization plays a role as well [17, 18]
Polyploidy, often tetraploidy, commonly originates from cell fusion or cytokinesis [3] though occurs through mitotic slippage induced by spindle assembly checkpoint (SAC)-dissatisfaction [7, 35]
Summary
A hallmark of transformed cells, is thought to drive tumorigenesis by favoring the generation of aggressive tumor cells with a reduced propensity for apoptosis [1]. Tetraploid cells are generated through a variety of mechanisms, including cytokinesis failure and viral-induced cell fusion [3]. Cells www.impactjournals.com/oncotarget can become tetraploidy after prolonged mitotic arrest by spindle assembly checkpoint (SAC), which functions to arrest mitotic cells with defects that prevent normal kinetochore–microtubule attachment [5]. Mitotic slippage occurs without karyokinesis and results in polyploidy cells with a single large nucleus, unlike cytokinesis failure and cell fusion, which give rise to binucleate cells [3]. Due to a weakened SAC, cells may slip out of mitotic arrest before they die; mitotic slippage protects cells from death and the resulting tetraploidy could pose a barrier to chemotherapy against malignancy [7,8,9]
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