Antiproliferative effects of γ-secretase inhibitor, a Notch signalling inhibitor, in multiple myeloma cells and its molecular mechanism of action

Abstract

Objectives: To investigate the effects of g-secretase inhibitor (GSI), a Notch signalling inhibitor, on the proliferation of multiple myeloma cells in vitro and its molecular mechanism of action. Methods: RPMI 8226 cells were treated with increasing concentrations of GSI (0-20 mmol/l) for 24-72 h. Proliferation was measured using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT) assay. Cell-cycle analysis was performed on RPMI 8226 cells treated with 0-10 μmol/l GSI for 48 h using flow cytometry. Expression of Notch signalling proteins (Notch1, Jagged 1 and Jagged 2), Bcl-2 and phosphorylated Akt (p-Akt) was determined using Western blotting in RPMI 8226 cells treated with various concentrations of GSI for various time periods. Results: GSI inhibited proliferation of RPMI 8226 cells in a concentration- and time-dependent manner by inducing G0/G1 cell-cycle arrest. GSI-mediated antiproliferative effects were associated with significant reductions in the expression of Notch1, Jagged1, Jagged2, p-Akt and Bcl-2. Conclusion: Inhibition of the Notch signalling pathway by GSI may be a promising therapeutic approach for the treatment of multiple myeloma. © The Author(s) 2013.