| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
We have synthesized and studied the ability of a series of seven novel 1
,25(OH)2 vitamin D3 analogues to inhibit clonal growth of prostate cancer cells (LNCaP, PC-3 and DU-145). Addition of double and triple bonds to the C/D ring (C-16) and side chain (C-22 and C-23) as well as lengthening of the side chain were important for enhanced activity against LNCaP and PC-3. Reorientation of the side chain in the 20-epi configuration resulted in analogues that were extremely potent only against LNCaP (ED50 
5 x 10–11 M). Compounds with six fluorines on the end of the side chain were very active against both PC-3 and LNCaP (ED50 2 x 10–8 M). DU-145 cells were relatively resistant to compounds with all of these modifications, but removal of C-19 (e.g. 1,25(OH)2-16-ene-23-yne-26,27-F6-19-nor-D3) resulted in an analogue that was inhibitory against all three prostate cell lines. Further analysis showed that pulse exposure (3 days, 10–7 M) to this analogue was enough to inhibit clonal growth of PC-3 cells by 50%. The same exposure also induced cell cycle arrest of all three cell lines, accompanied by upregulated protein expression of the cyclin-dependent kinase inhibitor (CDKI) known as p21waf1 in all three cell lines, and the CDKI known as p27kip1 in LNCaP cells. Associated with upregulation of these CDKIs, partial differentiation occurred as measured by increased expression of both prostate-specific antigen by LNCaP cells and E-cadherin, a cell adhesion protein that may act as a putative tumour suppressor (LNCaP and PC-3 cells). In summary, this is the first report of a potent series of 19-nor-vitamin D3 analogues with the ability to inhibit proliferation of LNCaP, PC-3 and DU-145 prostate cancer cell lines. These compounds may mediate their potent anti-proliferative activities through a cell cycle arrest pathway.
This article has been cited by other articles:
|
|
 |
|
  I. Chung, M. K. Wong, G. Flynn, W.-d. Yu, C. S. Johnson, and D. L. Trump Differential Antiproliferative Effects of Calcitriol on Tumor-Derived and Matrigel-Derived Endothelial Cells. Cancer Res., September 1, 2006; 66(17): 8565 - 8573. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Banwell, D. P. MacCartney, M. Guy, A. E. Miles, M. R. Uskokovic, J. Mansi, P. M. Stewart, L. P. O'Neill, B. M. Turner, K. W. Colston, et al. Altered nuclear receptor corepressor expression attenuates vitamin d receptor signaling in breast cancer cells. Clin. Cancer Res., April 1, 2006; 12(7): 2004 - 2013. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nagpal, S. Na, and R. Rathnachalam Noncalcemic Actions of Vitamin D Receptor Ligands Endocr. Rev., August 1, 2005; 26(5): 662 - 687. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Ikezoe, S. Gery, D. Yin, J. O'Kelly, L. Binderup, N. Lemp, H. Taguchi, and H. P. Koeffler CCAAT/Enhancer-Binding Protein {delta}: A Molecular Target of 1,25-Dihydroxyvitamin D3 in Androgen-Responsive Prostate Cancer LNCaP Cells Cancer Res., June 1, 2005; 65(11): 4762 - 4768. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. G. Schwartz, D. Eads, A. Rao, S. D. Cramer, M. C. Willingham, T. C. Chen, D. P. Jamieson, L. Wang, K. L. Burnstein, M. F. Holick, et al. Pancreatic cancer cells express 25-hydroxyvitamin D-1{alpha}-hydroxylase and their proliferation is inhibited by the prohormone 25-hydroxyvitamin D3 Carcinogenesis, June 1, 2004; 25(6): 1015 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. M. Beer and A. Myrthue Calcitriol in cancer treatment: From the lab to the clinic Mol. Cancer Ther., March 1, 2004; 3(3): 373 - 381. [Abstract] [Full Text]
|
|
|
|
 |
|
 E. S. Yang and K. L. Burnstein Vitamin D Inhibits G1 to S Progression in LNCaP Prostate Cancer Cells through p27Kip1 Stabilization and Cdk2 Mislocalization to the Cytoplasm J. Biol. Chem., November 21, 2003; 278(47): 46862 - 46868. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. C. Polek, L. V. Stewart, E. J. Ryu, M. B. Cohen, E. A. Allegretto, and N. L. Weigel p53 Is Required for 1,25-Dihydroxyvitamin D3-Induced G0 Arrest But Is Not Required for G1 Accumulation or Apoptosis of LNCaP Prostate Cancer Cells Endocrinology, January 1, 2003; 144(1): 50 - 60. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. N. Wade, M. C. Willingham, C. Koumenis, and S. D. Cramer p27Kip1 Is Essential for the Antiproliferative Action of 1,25-Dihydroxyvitamin D3 in Primary, but Not Immortalized, Mouse Embryonic Fibroblasts J. Biol. Chem., September 27, 2002; 277(40): 37301 - 37306. [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]
|
|
|
|
|
|
K. A. Moffatt, W. U. Johannes, T. E. Hedlund, and G. J. Miller Growth Inhibitory Effects of 1{alpha}, 25-Dihydroxyvitamin D3 Are Mediated by Increased Levels of p21 in the Prostatic Carcinoma Cell Line ALVA-31 Cancer Res., October 1, 2001; 61(19): 7122 - 7129. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Jensen, M. W. Madsen, J. Lukas, L. Binderup, and J. Bartek Inhibitory Effects of 1{alpha},25-Dihydroxyvitamin D3 on the G1-S Phase-Controlling Machinery Mol. Endocrinol., August 1, 2001; 15(8): 1370 - 1380. [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]
|
|
|
|
|
|
J.-Y. Hsu, D. Feldman, J. E. McNeal, and D. M. Peehl Reduced 1{{alpha}}-hydroxylase Activity in Human Prostate Cancer Cells Correlates with Decreased Susceptibility to 25-Hydroxyvitamin D3-induced Growth Inhibition Cancer Res., April 1, 2001; 61(7): 2852 - 2856. [Abstract] [Full Text]
|
|
|
|
|
|
X.-Y. Zhao, D. M. Peehl, N. M. Navone, and D. Feldman 1{alpha},25-Dihydroxyvitamin D3 Inhibits Prostate Cancer Cell Growth by Androgen-Dependent and Androgen-Independent Mechanisms Endocrinology, July 1, 2000; 141(7): 2548 - 2556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. W. Kensler, P. M. Dolan, S. J. Gange, J.-K. Lee, Q. Wang, and G. H. Posner Conceptually new deltanoids (vitamin D analogs) inhibit multistage skin tumorigenesis Carcinogenesis, July 1, 2000; 21(7): 1341 - 1345. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. C. Chen, G. G. Schwartz, K. L. Burnstein, B. L. Lokeshwar, and M. F. Holick The in Vitro Evaluation of 25-Hydroxyvitamin D3 and 19-nor-1{{alpha}},25-Dihydroxyvitamin D2 as Therapeutic Agents for Prostate Cancer Clin. Cancer Res., March 1, 2000; 6(3): 901 - 908. [Abstract] [Full Text]
|
|
|
|
|
|
D. Feldman, X.-Y. Zhao, and A. V. Krishnan Editorial/Mini-Review: Vitamin D and Prostate Cancer Endocrinology, January 1, 2000; 141(1): 5 - 9. [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
P. A. Hershberger, R. A. Modzelewski, Z. R. Shurin, R. M. Rueger, D. L. Trump, and C. S. Johnson 1,25-Dihydroxycholecalciferol (1,25-D3) Inhibits the Growth of Squamous Cell Carcinoma and Down-Modulates p21Waf1/Cip1 in Vitro and in Vivo Cancer Res., June 1, 1999; 59(11): 2644 - 2649. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. H. Ly, X.-Y. Zhao, L. Holloway, and D. Feldman Liarozole Acts Synergistically with 1{alpha},25-Dihydroxyvitamin D3 to Inhibit Growth of DU 145 Human Prostate Cancer Cells by Blocking 24-Hydroxylase Activity Endocrinology, May 1, 1999; 140(5): 2071 - 2076. [Abstract] [Full Text]
|
|
|
|
|
|
E. Pötter, C. Bergwitz, and G. Brabant The Cadherin-Catenin System: Implications for Growth and Differentiation of Endocrine Tissues Endocr. Rev., April 1, 1999; 20(2): 207 - 239. [Abstract] [Full Text]
|
|
|
|
|
|
X.-Y. Zhao, L. H. Ly, D. M. Peehl, and D. Feldman Induction of Androgen Receptor by 1{alpha},25-Dihydroxyvitamin D3 and 9-cis Retinoic Acid in LNCaP Human Prostate Cancer Cells Endocrinology, March 1, 1999; 140(3): 1205 - 1212. [Abstract] [Full Text]
|
|
|
|
|
|
K. A. Moffatt, W. U. Johannes, and G. J. Miller 1{{alpha}},25-Dihydroxyvitamin D3 and Platinum Drugs Act Synergistically to Inhibit the Growth of Prostate Cancer Cell Lines Clin. Cancer Res., March 1, 1999; 5(3): 695 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Ruijter, C. van de Kaa, G. Miller, D. Ruiter, F. Debruyne, and J. Schalken Molecular Genetics and Epidemiology of Prostate Carcinoma Endocr. Rev., February 1, 1999; 20(1): 22 - 45. [Abstract] [Full Text]
|
|
|
|
|
|
M. J. Campbell, S. Park, M. R. Uskokovic, M. I. Dawson, and H. P. Koeffler Expression of Retinoic Acid Receptor-{beta} Sensitizes Prostate Cancer Cells to Growth Inhibition Mediated by Combinations of Retinoids and a 19-nor Hexafluoride Vitamin D3 Analog Endocrinology, April 1, 1998; 139(4): 1972 - 1980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. F. McGuire, D. L. Trump, and C. S. Johnson Vitamin D3-induced Apoptosis of Murine Squamous Cell Carcinoma Cells. SELECTIVE INDUCTION OF CASPASE-DEPENDENT MEK CLEAVAGE AND UP-REGULATION OF MEKK-1 J. Biol. Chem., July 6, 2001; 276(28): 26365 - 26373. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
