Novel vitamin D analogs as potential therapeutics: Metabolism, toxicity profiling, and antiproliferative activity

J. Chen, J. Wang, T. Kim, Elaine Tieu, Edith Tang, Z. Lin, D. Kovacic, D.D. Miller, A.E. Postlethwaite, Robert Tuckey, A.T. Słomiński, W. Li.

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Aim: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics. Materials and Methods: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism. Results: 20S-And 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 ìg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes. Conclusion: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.
Original languageEnglish
Pages (from-to)2153-2164
JournalAnticancer Research
Volume34
Issue number5
Publication statusPublished - 2014

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Vitamin D
Calcitriol Receptors
Liver Microsomes
Enzymes
Keratinocytes
Cytoplasm
Therapeutics
20-hydroxyvitamin D3
In Vitro Techniques

Cite this

Chen, J. ; Wang, J. ; Kim, T. ; Tieu, Elaine ; Tang, Edith ; Lin, Z. ; Kovacic, D. ; Miller, D.D. ; Postlethwaite, A.E. ; Tuckey, Robert ; Słomiński, A.T. ; Li., W. / Novel vitamin D analogs as potential therapeutics: Metabolism, toxicity profiling, and antiproliferative activity. In: Anticancer Research. 2014 ; Vol. 34, No. 5. pp. 2153-2164.
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abstract = "Aim: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics. Materials and Methods: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism. Results: 20S-And 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 {\`i}g/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes. Conclusion: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.",
author = "J. Chen and J. Wang and T. Kim and Elaine Tieu and Edith Tang and Z. Lin and D. Kovacic and D.D. Miller and A.E. Postlethwaite and Robert Tuckey and A.T. Słomiński and W. Li.",
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Chen, J, Wang, J, Kim, T, Tieu, E, Tang, E, Lin, Z, Kovacic, D, Miller, DD, Postlethwaite, AE, Tuckey, R, Słomiński, AT & Li., W 2014, 'Novel vitamin D analogs as potential therapeutics: Metabolism, toxicity profiling, and antiproliferative activity' Anticancer Research, vol. 34, no. 5, pp. 2153-2164.

Novel vitamin D analogs as potential therapeutics: Metabolism, toxicity profiling, and antiproliferative activity. / Chen, J.; Wang, J.; Kim, T.; Tieu, Elaine; Tang, Edith; Lin, Z.; Kovacic, D.; Miller, D.D.; Postlethwaite, A.E.; Tuckey, Robert; Słomiński, A.T.; Li., W.

In: Anticancer Research, Vol. 34, No. 5, 2014, p. 2153-2164.

Research output: Contribution to journalArticle

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T1 - Novel vitamin D analogs as potential therapeutics: Metabolism, toxicity profiling, and antiproliferative activity

AU - Chen, J.

AU - Wang, J.

AU - Kim, T.

AU - Tieu, Elaine

AU - Tang, Edith

AU - Lin, Z.

AU - Kovacic, D.

AU - Miller, D.D.

AU - Postlethwaite, A.E.

AU - Tuckey, Robert

AU - Słomiński, A.T.

AU - Li., W.

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N2 - Aim: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics. Materials and Methods: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism. Results: 20S-And 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 ìg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes. Conclusion: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.

AB - Aim: To discover novel [20(OH)D3] analogs as antiproliferative therapeutics. Materials and Methods: We studied in vitro liver microsome stability, in vivo toxicity using mice, vitamin D receptor (VDR) translocation, in vitro antiproliferative effect, CYP enzyme metabolism. Results: 20S-And 20R(OH)D3 had reasonable half-lives of 50 min and 30 min (average) respectively in liver microsomes. They were non-hypercalcemic at a high dose of 60 ìg/kg. Three new 20(OH)D3 analogs were designed, synthesized and tested. They showed higher or comparable potency for inhibition of proliferation of normal keratinocytes and in the induction of VDR translocation from cytoplasm to nucleus, compared to 1,25(OH)2D3. These new analogs demonstrated different degrees of metabolism through a range of vitamin D-metabolizing CYP enzymes. Conclusion: Their lack of calcemic toxicity at high doses and their high biological activity suggest that this novel 20(OH)D3 scaffold may represent a promising platform for further development of therapeutically-useful agents.

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