The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Abstract

Objective. Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536. Materials and Methods. We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents. Results. We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G 2 /M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells. Conclusions. Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma. Ó

Kinome-level screening identifies inhibition of polo-like kinase-1 (PLK1) as a target for enhancing non-viral transgene expression

“…However, inhibition of PLK1 with 3.3 μM HMN-214 almost completely arrested cells in the G 2 /M phase (93.6 ± 1.6%), while PLK1 inhibition with 25 nM BI 2536 also resulted in strong accumulation of the cell population (87.1 ± 5.0%) in the G2/M phase of the cell cycle. These results are consistent with the known PLK1 inhibition activity of the drugs [42,43].…”

In vitro targeting of Polo-like kinase 1 in bladder carcinoma

“…Synergistic effects of PLK1 inhibition have been described for combinations of BI 2536 with imatinib and nilotinib in chronic myelogenous leukemia cells, 22 for combinations with NVP-AEW541 (a small molecule inhibitor of insulinlike growth factor-1 receptor) in biliary tract cancer, 23 and when combined with bortezomib and dexamethasone in multiple myeloma. 24 Moreover, GW843682X synergistically potentiated the growth inhibition and apoptosis of leukemia cells when combined with tubulin depolymerizing agent vincristine 17 and with VP-16. 25 In our experimental model, association with CDDP, showed synergistic effects for all cell lines when combined with BI 2536, BI 6727, and GW843682X at all concentrations tested (CI < 1).…”

Deficient Spindle Assembly Checkpoint in Multiple Myeloma

“…In fact, several recent reports indicate that inhibitors of the mitotic Aurora kinases induce apoptosis in MM cells and could be useful in MM treatment [20], [21], [22], [23], [24]. Also PLK inhibitors could have potential anti-tumor activity in MM [25].…”