TY - JOUR
T1 - Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D 3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells
AU - Iglesias-Gato, Diego
AU - Zheng, Shasha
AU - Flanagan, John N.
AU - Jiang, Lan
AU - Kittaka, Atsushi
AU - Sakaki, Toshiyuki
AU - Yamamoto, Keiko
AU - Itoh, Toshimasa
AU - Lebrasseur, Nathan K.
AU - Norstedt, Gunnar
AU - Chen, Tai C.
N1 - Funding Information:
This study was supported by a Grant-in-Aid for Scientific Research (C) from Japan Society for the Promotion of Science (Nos. 19590016 and 21590022 to A.K.). D. Iglesias-Gato was supported by a postdoctoral fellowship, granted by the Alfornso Martín Escudero Foundation (Spain) . Support was also given from VR (2009-3738) and Cancerfonden (Sweden).
PY - 2011/11
Y1 - 2011/11
N2 - The active form of vitamin D 3, 1α,25-dihydroxyvitamin D 3(1α,25(OH) 2D 3), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH) 2D 3 therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-1α,25(OH) 2D 2 while being less calcemic has equivalent potency as 1α,25(OH) 2D 3 in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3- hydroxypropyl)-1α,25(OH) 2D 3 (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH) 2D 3 in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1α,25(OH) 2D 3 on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to 1α,25(OH) 2D 3, suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1α,25(OH) 2D 3. In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer.
AB - The active form of vitamin D 3, 1α,25-dihydroxyvitamin D 3(1α,25(OH) 2D 3), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH) 2D 3 therapeutic potential in treating cancers, numerous analogues have been synthesized with an attempt to increase anti-proliferative and/or decrease calcemic properties. Among these analogues, 19-nor-1α,25(OH) 2D 2 while being less calcemic has equivalent potency as 1α,25(OH) 2D 3 in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3- hydroxypropyl)-1α,25(OH) 2D 3 (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH) 2D 3 in inhibiting the proliferation of an immortalized normal prostate PZ-HPV-7 cells and the invasion of androgen insensitive PC-3 prostate cancer cells, respectively. In this study, we further investigated the effects of MART-10 and 1α,25(OH) 2D 3 on the dose- and time-dependent induction of CYP24A1 gene expression in PC-3 prostate cancer cells. We found that MART-10 induced CYP24A1 gene expression at a lower concentration with a longer duration compared to 1α,25(OH) 2D 3, suggesting that MART-10 is less susceptible to CYP24A1 degradation. Molecular docking model of human CYP24A1 and MART-10 indicates that its side chain is far away from the heme ion and is less likely to be hydroxylated by the enzyme. Furthermore, MART-10 was a more potent inhibitor of PC-3 cell proliferation and invasion compared to 1α,25(OH) 2D 3. In addition, MART-10 down-regulated matrix metalloproteinase-9 (MMP-9) expression which could be one mechanism whereby MART-10 influences cancer cell invasion. Finally, we observed that subcutaneous administration of MART-10 up-regulated the CYP24A1 mRNA expression in rat kidneys without affecting their plasma calcium levels. Thus, our findings demonstrate that MART-10 is biologically active in vivo and may be an effective vitamin D analogue for clinical trials to treat prostate cancer.
KW - Invasion
KW - PC-3
KW - Proliferation
KW - Prostate cancer
KW - Vitamin D analogue
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U2 - 10.1016/j.jsbmb.2011.08.010
DO - 10.1016/j.jsbmb.2011.08.010
M3 - Article
C2 - 21911059
AN - SCOPUS:81255142150
SN - 0960-0760
VL - 127
SP - 269
EP - 275
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3-5
ER -