The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-beta1 in NCI-H929 multiple myeloma cells

• Published in: International journal of oncology Vol. 20; no. 3; p. 533
• Main Authors: Park, Woo Hyun, Seol, Jae Goo, Kim, Eun Shil, Binderup, Lise, Koeffler, H Phillip, Kim, Byoung Kook, Lee, Young Yiul
• Format: Journal Article
• Language: English
• Published: Greece 01-03-2002
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis; bcl-2-Associated X Protein; Blotting, Northern; Blotting, Western; Calcitriol - analogs & derivatives; Calcitriol - pharmacology; Cell Division; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - biosynthesis; DNA-Binding Proteins - biosynthesis; Electrophoresis, Polyacrylamide Gel; G1 Phase; Humans; Intracellular Membranes - metabolism; MAP Kinase Signaling System; Membrane Potentials - drug effects; Multiple Myeloma - pathology; Poly(ADP-ribose) Polymerases - biosynthesis; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins c-bcl-2; Retinoblastoma Protein - biosynthesis; Retinoblastoma Protein - metabolism; Signal Transduction; Smad4 Protein; Trans-Activators - biosynthesis; Transforming Growth Factor beta - pharmacology; Transforming Growth Factor beta1; Tumor Cells, Cultured; Up-Regulation
• ISSN: 1019-6439

Previously, we reported that EB1089 inhibited the growth of NCI-H929 myeloma cells via cell cycle arrest and apoptosis. In the present study, we investigated whether a combined EB1089 and TGF-beta1 synergistically inhibited the cell proliferation of myeloma cell lines. While TGF-beta1 alone could not inhibit the proliferation of any of the tested myeloma cells, synergistic effect between EB1089 (1 x 10(-8) M) and TGF-beta1 (1 ng/ml) was observed in NCI-H929 cells. TGF-beta1 intensified the decreased expression of CDK2, CDK4, CDK6 and cyclin D1 in EB1089-treated NCI-H929 cells. However, these effects did not intensify to decrease CDK2 activity of EB1089-treated NCI-H929 cells, resulting in no difference in the extent of G1 arrest between EB1089- and both agents-treated cells. Remarkably, both agents synergistically induce apoptosis of NCI-H929 cells, which was accompanied with up-regulation of Bax, degradation of PARP and Rb proteins, and loss of mitochondrial transmembrane potential (deltapsim). EB1089 caused the induction of SMAD4, a mediator of TGF-beta1 signaling. In addition, a combined EB1089 and TGF-beta1 increased p21 and JNK/SAPK activity whereas neither EB1089 nor TGF-beta1 affected p21 and JNK/SAPK activity. Taken together, these results suggest that treatment with both EB1089 and TGF-beta1 synergistically inhibits the proliferation of NCI-H929 cells through apoptosis.