1α,25‐Dihydroxyvitamin D3‐3β‐(2)‐bromoacetate, an affinity labeling derivative of 1α,25‐dihydroxyvitamin D3 displays strong antiproliferative and cytotoxic behavior in prostate cancer cells

In this report we describe that 1,25(OH)2D3‐3‐BE, a VDR‐affinity labeling analog of 1,25(OH)2D3, showed strong and dose‐dependent growth‐inhibitory effect in several epithelial cells, i.e., keratinocytes (primary cells), MCF‐7 breast cancer, PC‐3, and LNCaP prostate cancer and PZ‐HPV‐7 immortalized normal prostate cell‐lines. Furthermore, 10−6 M of 1,25(OH)2D3‐3‐BE induced apoptosis specifically in LNCaP and PC‐3 cells; and the effect was much less pronounced at lower doses. We also showed that the effect (of 1,25(OH)2D3‐3‐BE) was not due to probable degradation (hydrolysis) of 1,25(OH)2D3‐3‐BE or random interaction of this molecule with cellular proteins. Tissue‐ or cell‐specific action of 1,25(OH)2D3 and its mimics is not common due to the ubiquitous nature of VDR. Furthermore, variable effects of 1,25(OH)2D3 and its analogs in various cell‐lines potentially limits their application as anticancer agents. We showed that 1,25(OH)2D3‐3‐BE displayed similar growth‐inhibitory and cytotoxic activities towards androgen sensitive LNCaP and androgen‐independent PC‐3 cell‐lines. Therefore, these results raise the possibility that 1,25(OH)2D3‐3‐BE or similar VDR‐cross linking analogs of 1,25(OH)2D3 might be considered for further development as potential candidates for prostate cancer. J. Cell. Biochem. 89: 909–916, 2003. © 2003 Wiley‐Liss, Inc.

[1]  M. Holick.  Vitamin D: A millenium perspective , 2003, Journal of cellular biochemistry.

[2]  N. Swamy,et al.  Affinity labeling of the nuclear vitamin D receptor with nonsteroidal alkylating agents. , 2003, Bioorganic & medicinal chemistry letters.

[3]  M. Holick.  VITAMIN D: A MILLENNIUM PERSPECTIVE , 2003 .

[4]  P. Hershberger,et al.  Vitamin D receptor: a potential target for intervention. , 2002, Urology.

[5]  G. V. D. van den Bemd,et al.  Vitamin D and vitamin D analogs in cancer treatment. , 2002, Current drug targets.

[6]  D. Moras,et al.  Crystal structures of the vitamin D receptor complexed to superagonist 20-epi ligands , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[7]  J. Welsh,et al.  Role of Mitochondria and Caspases in Vitamin D-mediated Apoptosis of MCF-7 Breast Cancer Cells* , 2001, The Journal of Biological Chemistry.

[8]  S. Mohr,et al.  Why do we need a three-dimensional architecture of the ligand-binding domain of the nuclear 1α,25-dihydroxyvitamin D3 receptor?☆ , 2001, Steroids.

[9]  D. Feldman,et al.  The role of vitamin D in prostate cancer , 2001, Steroids.

[10]  S. Mohr,et al.  Why do we need a three-dimensional architecture of the ligand-binding domain of the nuclear 1alpha,25-dihydroxyvitamin D(3) receptor? , 2001, Steroids.

[11]  M. Haussler,et al.  Molecular modeling, affinity labeling, and site-directed mutagenesis define the key points of interaction between the ligand-binding domain of the vitamin D nuclear receptor and 1 alpha,25-dihydroxyvitamin D3. , 2000, Biochemistry.

[12]  D. Moras,et al.  The crystal structure of the nuclear receptor for vitamin D bound to its natural ligand. , 2000, Molecular cell.

[13]  T. McDonnell,et al.  Printed in U.S.A. Copyright © 2000 by The Endocrine Society Calcitriol-Induced Apoptosis in LNCaP Cells Is Blocked By Overexpression of Bcl-2* , 1999 .

[14]  M. Holick,et al.  Mechanistic studies to evaluate the enhanced antiproliferation of human keratinocytes by 1alpha,25-dihydroxyvitamin D(3)-3-bromoacetate, a covalent modifier of vitamin D receptor, compared to 1alpha,25-dihydroxyvitamin D(3). , 1999, Archives of biochemistry and biophysics.

[15]  N. Weigel,et al.  Vitamin D and Prostate Cancer , 1999, Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine.

[16]  D. Feldman,et al.  Liarozole acts synergistically with 1alpha,25-dihydroxyvitamin D3 to inhibit growth of DU 145 human prostate cancer cells by blocking 24-hydroxylase activity. , 1999, Endocrinology.

[17]  H. DeLuca,et al.  Current understanding of the molecular actions of vitamin D. , 1998, Physiological reviews.

[18]  K. Burnstein,et al.  Antiproliferative Effect of 1α,25-Dihydroxyvitamin D3 in Human Prostate Cancer Cell Line LNCaP Involves Reduction of Cyclin-Dependent Kinase 2 Activity and Persistent G1 Accumulation. , 1998, Endocrinology.

[19]  M. Haussler,et al.  The Nuclear Vitamin D Receptor: Biological and Molecular Regulatory Properties Revealed , 1998, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[20]  N. Swamy,et al.  Identification of the subdomain in the nuclear receptor for the hormonal form of vitamin D3, 1 alpha,25-dihydroxyvitamin D3, vitamin D receptor, that is covalently modified by an affinity labeling reagent. , 1997, Archives of biochemistry and biophysics.

[21]  N. Swamy,et al.  Roles of the structure and orientation of ligands and ligand mimics inside the ligand-binding pocket of the vitamin D-binding protein. , 1997, Biochemistry.

[22]  H. Pols,et al.  Conformational change and enhanced stabilization of the vitamin D receptor by the 1,25-dihydroxyvitamin D3 analog KH1060. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Welsh,et al.  1,25-Dihydroxyvitamin D3 induces morphological and biochemical markers of apoptosis in MCF-7 breast cancer cells , 1996, The Journal of Steroid Biochemistry and Molecular Biology.

[24]  M. Haussler,et al.  Affinity Labeling of the 1,25-Dihydroxyvitamin D Receptor (*) , 1996, The Journal of Biological Chemistry.

[25]  L. Freedman,et al.  Transcriptional activation of the Cdk inhibitor p21 by vitamin D3 leads to the induced differentiation of the myelomonocytic cell line U937. , 1996, Genes & development.

[26]  A. Norman,et al.  Distinct Conformational Changes Induced by 20-epi Analogues of 1,25-Dihydroxyvitamin D Are Associated with Enhanced Activation of the Vitamin D Receptor (*) , 1995, The Journal of Biological Chemistry.

[27]  D. Peehl,et al.  Actions of vitamin D3, analogs on human prostate cancer cell lines: comparison with 1,25-dihydroxyvitamin D3. , 1995, Endocrinology.

[28]  M. Holick,et al.  1α,25-Dihydroxyvitamin D3-3β-bromoacetate, an Affinity-Labeling Analog of 1α,25-Dihydroxyvitamin D3 Receptor , 1994 .

[29]  J. Foekens,et al.  Vitamin D: A modulator of cell proliferation and differentiation , 1990, The Journal of Steroid Biochemistry and Molecular Biology.

[30]  Tadashi Kobayashi.  The Role of Vitamin D , 1988 .

[31]  H. Green,et al.  Seria cultivation of strains of human epidemal keratinocytes: the formation keratinizin colonies from single cell is , 1975, Cell.

[32]  H Green,et al.  Serial cultivation of strains of human epidermal keratinocytes: the formation of keratinizing colonies from single cells. , 1975, Cell.