Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells

Diego Iglesias Gato; Shasha Zheng; John N. Flanagan; Lan Jiang; Atsushi Kittaka; Toshiyuki Sakaki; Keiko Yamamoto; Toshimasa Itoh; Nathan K Lebrasseur; Gunnar Norstedt; Tai C Chen

doi:10.1016/j.jsbmb.2011.08.010

Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells

Diego Iglesias Gato, Shasha Zheng, John N. Flanagan, Lan Jiang, Atsushi Kittaka, Toshiyuki Sakaki, Keiko Yamamoto, Toshimasa Itoh, Nathan K Lebrasseur, Gunnar Norstedt, Tai C Chen

27 Citations (Scopus)

Abstract

The active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3)(1α,25(OH)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(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)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(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.

Original language	English
Journal	Journal of Steroid Biochemistry and Molecular Biology
Volume	127
Issue number	3-5
Pages (from-to)	269-75
Number of pages	7
ISSN	0960-0760
DOIs	https://doi.org/10.1016/j.jsbmb.2011.08.010
Publication status	Published - Nov 2011
Externally published	Yes

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Iglesias Gato, D., Zheng, S., Flanagan, J. N., Jiang, L., Kittaka, A., Sakaki, T., Yamamoto, K., Itoh, T., Lebrasseur, N. K., Norstedt, G., & Chen, T. C. (2011). Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells. Journal of Steroid Biochemistry and Molecular Biology, 127(3-5), 269-75. https://doi.org/10.1016/j.jsbmb.2011.08.010

Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells. / Iglesias Gato, Diego; Zheng, Shasha; Flanagan, John N. et al.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 127, No. 3-5, 11.2011, p. 269-75.

Research output: Contribution to journal › Journal article › Research › peer-review

Iglesias Gato, D, Zheng, S, Flanagan, JN, Jiang, L, Kittaka, A, Sakaki, T, Yamamoto, K, Itoh, T, Lebrasseur, NK, Norstedt, G & Chen, TC 2011, 'Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells', Journal of Steroid Biochemistry and Molecular Biology, vol. 127, no. 3-5, pp. 269-75. https://doi.org/10.1016/j.jsbmb.2011.08.010

@article{cfe8cd836da54146825d0a3f8e4c980f,

title = "Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells",

abstract = "The active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3)(1α,25(OH)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(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)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(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.",

keywords = "Antineoplastic Agents, Blotting, Western, Calcitriol, Carbon, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Enzymologic, Humans, Hydroxylation, Male, Prostatic Neoplasms, Real-Time Polymerase Chain Reaction, Steroid Hydroxylases, Vitamin D3 24-Hydroxylase",

author = "{Iglesias Gato}, Diego and Shasha Zheng and Flanagan, {John N.} and Lan Jiang and Atsushi Kittaka and Toshiyuki Sakaki and Keiko Yamamoto and Toshimasa Itoh and Lebrasseur, {Nathan K} and Gunnar Norstedt and Chen, {Tai C}",

year = "2011",

month = nov,

doi = "10.1016/j.jsbmb.2011.08.010",

language = "English",

volume = "127",

pages = "269--75",

journal = "Journal of Steroid Biochemistry and Molecular Biology",

issn = "0960-0760",

publisher = "Pergamon Press",

number = "3-5",

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TY - JOUR

T1 - Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 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

PY - 2011/11

Y1 - 2011/11

N2 - The active form of vitamin D(3), 1α,25-dihydroxyvitamin D(3)(1α,25(OH)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(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)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(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)(2)D(3)), has anti-proliferative and anti-invasive activities in prostate cancer cells. Because of 1α,25(OH)(2)D(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)(2)D(2) while being less calcemic has equivalent potency as 1α,25(OH)(2)D(3) in several in vitro and in vivo systems. We recently showed that 19-nor-2α-(3-hydroxypropyl)-1α,25(OH)(2)D(3) (MART-10) was at least 500-fold and 10-fold more active than 1α,25(OH)(2)D(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)(2)D(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)(2)D(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)(2)D(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 - Antineoplastic Agents

KW - Blotting, Western

KW - Calcitriol

KW - Carbon

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Gene Expression Regulation, Enzymologic

KW - Humans

KW - Hydroxylation

KW - Male

KW - Prostatic Neoplasms

KW - Real-Time Polymerase Chain Reaction

KW - Steroid Hydroxylases

KW - Vitamin D3 24-Hydroxylase

U2 - 10.1016/j.jsbmb.2011.08.010

DO - 10.1016/j.jsbmb.2011.08.010

M3 - Journal article

C2 - 21911059

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 -

Substitution at carbon 2 of 19-nor-1α,25-dihydroxyvitamin D3 with 3-hydroxypropyl group generates an analogue with enhanced chemotherapeutic potency in PC-3 prostate cancer cells

Abstract

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