TY - JOUR
T1 - Anti-proliferative effects of 20-epi-vitamin-D3 analogue, KH1060 in human neuroblastoma
T2 - Induction of RAR-β and p21Cip1
AU - Gumireddy, Kiranmai
AU - Reddy, G. S.
AU - Ikegaki, Naohiko
AU - Binderup, Lise
AU - Sutton, Leslie N.
AU - Phillips, Peter C.
AU - Reddy, C. Damodar
N1 - Funding Information:
This project is supported by grants from Joseph Stokes Research Institute to C.D.R. Also supported by Louis Vastardis Neurosurgical Research Fund to L.N.S. and Jeoffrey Miller Neuro-Oncology Research Fund to P.C.P. We thank Asha Guttapalli for help in preparing the manuscript.
PY - 2003/2/10
Y1 - 2003/2/10
N2 - We determined the in vitro biological activities of 1α, 25-dihdroxyvitamin D3 (1,25-D3) and its analogue, 20-epi-22-oxa-24a, 26a, 27a-trihomo-1 α, 25 (OH)2 vitamin D3 (KH1060) in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP-134, NGP). The ability of these compounds to inhibit cell growth and DNA synthesis was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and BrdU incorporation, respectively. The induction of cell death was monitored by caspase-3 activity. Their antineoplastic effect was assessed by clonal proliferation in soft agar. KH1060 was more effective than 1,25 D3 in inhibiting cell growth and DNA synthesis. The IC-50 (inhibition of 50% cell viability) indicated that KH1060 was about 10-20-fold more potent than 1,25 D3. This growth inhibition was also accompanied by induction of caspase-3 activity, indicating that these compounds induce cell death in a caspase-dependent fashion. Moreover, KH1060 exerted potent antineoplastic activity by suppressing the clonal proliferation of the six NB cells. For the first time we demonstrate that KH1060 induces the expression of retinoic acid receptor-β and p21Cip1 suggesting that these proteins in part mediate the growth inhibitory effects. Taken together, all the six NB cells were more susceptible to growth inhibition by KH1060 than 1,25-D3, suggesting its possible use in NB to potentiate the action of retinoids, which are in clinical use for this disease.
AB - We determined the in vitro biological activities of 1α, 25-dihdroxyvitamin D3 (1,25-D3) and its analogue, 20-epi-22-oxa-24a, 26a, 27a-trihomo-1 α, 25 (OH)2 vitamin D3 (KH1060) in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP-134, NGP). The ability of these compounds to inhibit cell growth and DNA synthesis was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and BrdU incorporation, respectively. The induction of cell death was monitored by caspase-3 activity. Their antineoplastic effect was assessed by clonal proliferation in soft agar. KH1060 was more effective than 1,25 D3 in inhibiting cell growth and DNA synthesis. The IC-50 (inhibition of 50% cell viability) indicated that KH1060 was about 10-20-fold more potent than 1,25 D3. This growth inhibition was also accompanied by induction of caspase-3 activity, indicating that these compounds induce cell death in a caspase-dependent fashion. Moreover, KH1060 exerted potent antineoplastic activity by suppressing the clonal proliferation of the six NB cells. For the first time we demonstrate that KH1060 induces the expression of retinoic acid receptor-β and p21Cip1 suggesting that these proteins in part mediate the growth inhibitory effects. Taken together, all the six NB cells were more susceptible to growth inhibition by KH1060 than 1,25-D3, suggesting its possible use in NB to potentiate the action of retinoids, which are in clinical use for this disease.
KW - Antiproliferation
KW - Neuroblastoma
KW - Retinoic acid receptor-β
KW - Vitamin D analogues
UR - http://www.scopus.com/inward/record.url?scp=0037428896&partnerID=8YFLogxK
U2 - 10.1016/S0304-3835(02)00551-7
DO - 10.1016/S0304-3835(02)00551-7
M3 - Article
C2 - 12536077
AN - SCOPUS:0037428896
SN - 0304-3835
VL - 190
SP - 51
EP - 60
JO - Cancer Letters
JF - Cancer Letters
IS - 1
ER -