The authors have no conflict of interest to declare.
Potent Antiproliferative Effects of 25-Hydroxy-16-ene-23-yne-vitamin D3 That Resists the Catalytic Activity of Both CYP27B1 and CYP24A1
Article first published online: 17 JUN 2014
© 2014 Wiley Periodicals, Inc.
Journal of Cellular Biochemistry
Volume 115, Issue 8, pages 1392–1402, August 2014
How to Cite
Rhieu, S. Y., Annalora, A. J., LaPorta, E., Welsh, J., Itoh, T., Yamamoto, K., Sakaki, T., Chen, T. C., Uskokovic, M. R. and Reddy, G. S. (2014), Potent Antiproliferative Effects of 25-Hydroxy-16-ene-23-yne-vitamin D3 That Resists the Catalytic Activity of Both CYP27B1 and CYP24A1. J. Cell. Biochem., 115: 1392–1402. doi: 10.1002/jcb.24789
- Issue published online: 17 JUN 2014
- Article first published online: 17 JUN 2014
- Accepted manuscript online: 18 FEB 2014 05:51AM EST
- Manuscript Accepted: 14 FEB 2014
- Manuscript Received: 5 FEB 2014
- Epimer LLC
- The National Cancer Institute. Grant Number: R01CA69700
- VITAMIN D;
- ANTIPROLIFERATIVE ACTIVITY
The potency of 25-hydroxyvitamin D3 (25(OH)D3) is increased by several fold through its metabolism into 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) by cytochrome P450 27B1 (CYP27B1). Thus, the pivotal role of 1α-hydroxylation in the activation of vitamin D compounds is well known. Here, we examined the metabolism of 25-hydroxy-16-ene-23-yne-vitamin D3 (25(OH)-16-ene-23-yne-D3), a synthetic analog of 25(OH)D3 in a cell-free system and demonstrated that 25(OH)-16-ene-23-yne-D3 is neither activated by CYP27B1 nor inactivated by cytochrome P450 24A1 (CYP24A1). These findings were also confirmed in immortalized normal human prostate epithelial cells (PZ-HPV-7) which are known to express both CYP27B1 and CYP24A1, indicating that the structural modifications featured in 25(OH)-16-ene-23-yne-D3 enable the analog to resist the actions of both CYP27B1 and CYP24A1. To provide intelligible structure-function information, we also performed molecular docking analysis between the analog and CYP27B1. Furthermore, 25(OH)-16-ene-23-yne-D3 was found to suppress the growth of PZ-HPV-7 cells with a potency equivalent to 1α,25(OH)2D3. The antiproliferative activity of 25(OH)-16-ene-23-yne-D3 was found to be vitamin D receptor (VDR)-dependent as it failed to inhibit the growth of mammary tumor cells derived from VDR-knockout mice. Furthermore, stable introduction of VDR into VDR-knockout cells restored the growth inhibition by 25(OH)-16-ene-23-yne-D3. Thus, we identified 25-hydroxy-16-ene-23-yne-vitamin D3 as a novel non-1α-hydroxylated vitamin D analog which is equipotent to 1α,25(OH)2D3 in its antiproliferative activity. We now propose that the low potency of the intrinsic VDR-mediated activities of 25(OH)D3 can be augmented to the level of 1α,25(OH)2D3 without its activation through 1α-hydroxylation by CYP27B1, but by simply preventing its inactivation by CYP24A1. J. Cell. Biochem. 115: 1392–1402, 2014. © 2014 Wiley Periodicals, Inc.