title: The induction of apoptosis by a combined 1,25(OH)2D3 analog, EB1089 and TGF-beta1 in NCI-H929 multiple myeloma cells.
abstract: 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.
authors.affiliation: Cancer Research Institute and Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, Korea.
authors.forename: Woo Hyun
authors.initials: WH
authors.lastname: Park
authors.forename: Jae Goo
authors.initials: JG
authors.lastname: Seol
authors.forename: Eun Shil
authors.initials: ES
authors.lastname: Kim
authors.forename: Lise
authors.initials: L
authors.lastname: Binderup
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
authors.forename: Byoung Kook
authors.initials: BK
authors.lastname: Kim
authors.forename: Young Yiul
authors.initials: YY
authors.lastname: Lee
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002455:Cell Division; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D004591:Electrophoresis, Polyacrylamide Gel; D016193:G1 Phase; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008564:Membrane Potentials / Q000187:drug effects; D009101:Multiple Myeloma / Q000473:pathology*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein; D015534:Trans-Activators / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D053773:Transforming Growth Factor beta1; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D051028:bcl-2-Associated X Protein
chemical_list: D000970:Antineoplastic Agents; C494826:BAX protein, human; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016160:Retinoblastoma Protein; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C508960:TGFB1 protein, human; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; D011065:Poly(ADP-ribose) Polymerases; D002117:Calcitriol; C078903:seocalcitol