کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1963485 | 1058453 | 2013 | 10 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Bendamustine overcomes resistance to melphalan in myeloma cell lines by inducing cell death through mitotic catastrophe Bendamustine overcomes resistance to melphalan in myeloma cell lines by inducing cell death through mitotic catastrophe](/preview/png/1963485.png)
Melphalan has been a mainstay of multiple myeloma (MM) therapy for many years. However, following treatment with this alkylator, malignant plasma cells usually escape both apoptosis and cell cycle control, and acquire drug-resistance resulting in tumor progression. Bendamustine is being used in MM patients refractory to conventional DNA-damaging agents, although the mechanisms driving this lack of cross-resistance are still undefined. Here, we investigated the molecular pathway of bendamustine-induced cell death in melphalan-sensitive and melphalan-resistant MM cell lines. Bendamustine affected cell survival resulting in secondary necrosis, and prompted cell death primarily through caspase-2 activation. Also, bendamustine blocked the cell cycle in the G2/M phase and induced micronucleation, erratic chromosome spreading and mitotic spindle perturbations in melphalan-resistant MM cells. In these cells, both Aurora kinase A (AURKA) and Polo-like kinase-1 (PLK-1), key components of the spindle-assembly checkpoint, were down-regulated following incubation with bendamustine, whereas levels of Cyclin B1 increased as a consequence of the prolonged mitotic arrest induced by the drug. These findings indicate that, at least in vitro, bendamustine drives cell death by promoting mitotic catastrophe in melphalan-resistant MM cells. Hence, activation of this alternative pathway of cell death may be a novel approach to the treatment of apoptosis-resistant myelomas.
► Bendamustine induces mitotic catastrophe (MC) in multiple myeloma cell lines.
► Activation of MC is useful for treating apoptosis-deficient myeloma cells.
► Initiation of MC offers a valuable strategy in the treatment of relapsing myelomas.
Journal: Cellular Signalling - Volume 25, Issue 5, May 2013, Pages 1108–1117