title: Bendamustine overcomes resistance to melphalan in myeloma cell lines by inducing cell death through mitotic catastrophe.
abstract: 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.
authors: Department of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, Piazza Giulio Cesare 11, 70124 Bari, Italy.
authors: Mauro
authors: M
authors: Cives
authors: Sabino
authors: S
authors: Ciavarella
authors: Francesca Maria
authors: FM
authors: Rizzo
authors: Monica
authors: M
authors: De Matteo
authors: Franco
authors: F
authors: Dammacco
authors: Franco
authors: F
authors: Silvestris
mesh_terms: D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D064096:Aurora Kinase A; D064127:Aurora Kinases; D000069461:Bendamustine Hydrochloride; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D056744:Cyclin B1 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D008558:Melphalan / Q000494:pharmacology*; D008938:Mitosis; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D000097869:Polo-Like Kinase 1
chemical_list: D018906:Antineoplastic Agents, Alkylating; D064096:Aurora Kinase A; D064127:Aurora Kinases; D000069461:Bendamustine Hydrochloride; D018797:Cell Cycle Proteins; D056744:Cyclin B1; D008558:Melphalan; D009588:Nitrogen Mustard Compounds; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1; C576917:AURKA protein, human