|
|
 Previous Article | Table of Contents | Next Article 
A new series of vitamin D analogs is highly active for clonal inhibition,
differentiation, and induction of WAF1 in myeloid leukemia
R Munker, T Kobayashi, E Elstner, AW Norman, M Uskokovic, W Zhang, M Andreeff and HP Koeffler
Division of Hematology/Oncology, Cedars-Sinai Medical Center/UCLA School of
Medicine 90048, USA.
The active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha,
25(OH)2D3)] modulates the proliferation and differentiation of
hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater
potency may have the potential as adjuvant therapy for high-risk patients
in remission for acute myelogenous leukemia (AML) and myelodysplastic
syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been
synthesized, and we examined their effects on the human leukemic cell line
HL-60. This cell line provides a sensitive monitor of activity of the 1
alpha, 25(OH)2D3 analogs. All the compounds were potent, producing a 50%
clonal inhibition (ED50) in the range of 10(-8) to 10(-11) mol/L; nine of
the 11 analogs had ED50s at concentrations that were at least 10-fold lower
than those for the parental 1,25(OH)2D3. The most active compound [cmpd LA,
(22R)-1 alpha, 25-(OH)2-16,22,23-triene-D3] had an ED50 of 2 x 10(-11)
mol/L; it was also tested on clonogenic cells from patients with AML, and
it achieved an ED50 of approximately 6 x 10(-11) mol/L, while 1 alpha,
25(OH)2D3 produced an ED50 of approximately 10(-8) mol/L on the same
population of cells. Five different cell surface markers were examined on
HL-60 cells exposed to the 1 alpha, 25(OH)2D3 analogs: HLA-DR and CD11b
were induced by all of the compounds; CD13 was induced by six of the 12
compounds, including 1,25(OH)2D3; CD14 was strongly induced by all
compounds; and CD38 was induced rather weakly by nine of 12 analogs.
WAF1/CIP1/p21, a cyclin-dependent kinase inhibitor (CDKI), which is
important in blocking the cell cycle, was examined by Western blot and was
found to be induced by all of the compounds, suggesting a possible
mechanism by which these analogs inhibit leukemic growth. The induction of
WAF1 occurred at concentrations of vitamin D analogs as low as 10(- 10)
mol/L. This structure-function study showed that a new series of 1 alpha,
25(OH)2D3 analogs was active in clonal inhibition, as well as induction of
differentiation and WAF1 expression of HL-60 cells. The key structural
motifs included C-16 double bond, double and/or triple bonds in the side
chain, lengthening of the side chain, 20-epi- conformation of the side
chain, replacement of six hydrogens at the end of the side chain with
fluorines, and the removal of C-19. Consideration should be given to
further in vivo testing of toxicity and efficacy to move toward a clinical
trial, especially in a setting of minimal residual disease.
Volume 88,
Issue 6,
pp. 2201-2209,
09/15/1996
Copyright © 1996 by The American Society of Hematology
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
J. Correale, M. C. Ysrraelit, and M. I. Gaitan
Immunomodulatory effects of Vitamin D in multiple sclerosis
Brain,
May 1, 2009;
132(5):
1146 - 1160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Chen, G. P. Sims, X. X. Chen, Y. Y. Gu, S. Chen, and P. E. Lipsky
Modulatory Effects of 1,25-Dihydroxyvitamin D3 on Human B Cell Differentiation
J. Immunol.,
August 1, 2007;
179(3):
1634 - 1647.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Nakagawa, Y. Sasaki, S. Kato, N. Kubodera, and T. Okano
22-Oxa-1{alpha},25-dihydroxyvitamin D3 inhibits metastasis and angiogenesis in lung cancer
Carcinogenesis,
June 1, 2005;
26(6):
1044 - 1054.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Li, C. Li, X. Zhao, X. Zhang, S. V. Nicosia, and W. Bai
p27Kip1 Stabilization and G1 Arrest by 1,25-Dihydroxyvitamin D3 in Ovarian Cancer Cells Mediated through Down-regulation of Cyclin E/Cyclin-dependent Kinase 2 and Skp1-Cullin-F-box Protein/Skp2 Ubiquitin Ligase
J. Biol. Chem.,
June 11, 2004;
279(24):
25260 - 25267.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Kumagai, J. O'Kelly, J. W. Said, and H. P. Koeffler
Vitamin D2 Analog 19-nor-1,25-Dihydroxyvitamin D2: Antitumor Activity Against Leukemia, Myeloma, and Colon Cancer Cells
J Natl Cancer Inst,
June 18, 2003;
95(12):
896 - 905.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Lin, T. T. Wang, W. H. Miller Jr., and J. H. White
Inhibition of F-Box Protein p45SKP2 Expression and Stabilization of Cyclin-Dependent Kinase Inhibitor p27KIP1 in Vitamin D Analog-Treated Cancer Cells
Endocrinology,
March 1, 2003;
144(3):
749 - 753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Lin, Y. Nagai, R. Sladek, Y. Bastien, J. Ho, K. Petrecca, G. Sotiropoulou, E. P. Diamandis, T. J. Hudson, and J. H. White
Expression Profiling in Squamous Carcinoma Cells Reveals Pleiotropic Effects of Vitamin D3 Analog EB1089 Signaling on Cell Proliferation, Differentiation, and Immune System Regulation
Mol. Endocrinol.,
June 1, 2002;
16(6):
1243 - 1256.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Huerta, R. W. Irwin, D. Heber, V. L. W. Go, H. P. Koeffler, M. R. Uskokovic, and D. M. Harris
1{alpha},25-(OH)2-D3 and Its Synthetic Analogue Decrease Tumor Load in the Apcmin Mouse
Cancer Res.,
February 1, 2002;
62(3):
741 - 746.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Akutsu, R. Lin, Y. Bastien, A. Bestawros, D. J. Enepekides, M. J. Black, and J. H. White
Regulation of Gene Expression by 1{{alpha}},25-Dihydroxyvitamin D3 and Its Analog EB1089 under Growth-Inhibitory Conditions in Squamous Carcinoma Cells
Mol. Endocrinol.,
July 1, 2001;
15(7):
1127 - 1139.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Prudencio, N. Akutsu, N. Benlimame, T. Wang, Y. Bastien, R. Lin, M. J. Black, M. A. Alaoui-Jamali, and J. H. White
Action of Low Calcemic 1{{alpha}},25-Dihydroxyvitamin D3 Analogue EB1089 in Head and Neck Squamous Cell Carcinoma
J Natl Cancer Inst,
May 16, 2001;
93(10):
745 - 753.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-i. Hisatake, J. O'Kelly, M. R. Uskokovic, S. Tomoyasu, and H. P. Koeffler
Novel vitamin D3 analog, 21-(3-methyl-3-hydroxy-butyl)-19-nor D3, that modulates cell growth, differentiation, apoptosis, cell cycle, and induction of PTEN in leukemic cells
Blood,
April 15, 2001;
97(8):
2427 - 2433.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Shiohara, M. Uskokovic, J. Hisatake, Y. Hisatake, K. Koike, A. Komiyama, and H. P. Koeffler
24-Oxo Metabolites of Vitamin D3 Analogues: Disassociation of Their Prominent Antileukemic Effects from Their Lack of Calcium Modulation
Cancer Res.,
April 1, 2001;
61(8):
3361 - 3368.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
G. Glorieux, C. Hsu, R. De Smet, A. Dhondt, J. van Emmelo, M.-A. Waterloos, N. Lameire, J. Plum, and R. Vanholder
The anti-proliferative effect of calcitriol on HL-60 cells is neutralized by uraemic biological fluids
Nephrol. Dial. Transplant.,
February 1, 2001;
16(2):
246 - 252.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Berry and K. A. Meckling-Gill
Vitamin D Analogs, 20-Epi-22-Oxa-24a,26a,27a,-Trihomo-1{alpha},25(OH)2-Vitamin D3, 1,24(OH)2-22-Ene-24-Cyclopropyl-Vitamin D3 and 1{alpha},25(OH)2-Lumisterol3 Prime NB4 Leukemia Cells for Monocytic Differentiation via Nongenomic Signaling Pathways, Involving Calcium and Calpain
Endocrinology,
October 1, 1999;
140(10):
4779 - 4788.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
J.-i. Hisatake, T. Kubota, Y. Hisatake, M. Uskokovic, S. Tomoyasu, and H. P. Koeffler
5,6-trans-16-ene-Vitamin D3: A New Class of Potent Inhibitors of Proliferation of Prostate, Breast, and Myeloid Leukemic Cells
Cancer Res.,
August 1, 1999;
59(16):
4023 - 4029.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. J. Sabet, S. R. Darjatmoko, M. J. Lindstrom, and D. M. Albert
Antineoplastic Effect and Toxicity of 1,25-Dihydroxy-16-ene-23-yne-vitamin D3 in Athymic Mice With Y-79 Human Retinoblastoma Tumors
Arch Ophthalmol,
March 1, 1999;
117(3):
365 - 370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
