Induction of apoptosis by vitamin D3 analogue EB1089 in NCI-H929 myeloma cells via activation of caspase 3 and p38 MAP kinase.
EB1089, a novel 1,25-dihydroxyvitamin D3 analogue, has been known to have potent antiproliferative properties in a variety of malignant cells both in vitro and in vivo. In the present study, we analysed the effect of EB1089 on NCI-H929 human myeloma cells. EB1089 inhibited cell growth of NCI-H929 and efficiently induced the G1 phase arrest of the cell cycle in a dose-dependent manner. We could also detect apoptosis in NCI-H929 cells exposed to EB1089 (1 x 10-7 M for 72 h) using the sub-G1 group of the cell cycle by FACS and annexin V binding assays. Induction of apoptosis by EB1089 was associated with down-regulation of the Bcl-2 protein without change of the Bax protein. Regarding caspase activity, which plays a crucial role in apoptosis, EB1089-treated NCI-H929 cells revealed an increased activity of caspase 3 protease accompanied by degradation of the PARP protein in a dose- and time-dependent manner. In addition, EB1089 caused the down-regulation of p44 extracellular signal-related kinase (ERK) activity and up-regulation of the p38 kinase activity during apoptosis of NCI-H929 cells. These results suggest that EB1089 inhibits growth of NCI-H929 cells via G1 cell cycle arrest as well as apoptosis by activating p38 kinase and suppressing ERK activity.
Park
W H
WH
Cancer Research Centre and Department of Internal Medicine, Seoul National University College of Medicine, Korea.
Seol
J G
JG
Kim
E S
ES
Hyun
J M
JM
Jung
C W
CW
Lee
C C
CC
Binderup
L
L
Koeffler
H P
HP
Kim
B K
BK
Lee
Y Y
YY
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002762:Cholecalciferol / Q000031:analogs & derivatives*; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D002762:Cholecalciferol; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D002117:Calcitriol; C078903:seocalcitol