Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity

Andrzej T. Slominski, Zorica Janjetovic, Brian E. Fuller, Michal A. Zmijewski, Robert C. Tuckey, Minh N. Nguyen, Trevor Sweatman, Wei Li, Jordan Zjawiony, Duane Miller, Tai C. Chen, Gerard Lozanski, Michael F. Holick

Research output: Contribution to journalArticle

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Abstract

Background: Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH) 2 D3, as well as 1-hydroxyvitamin D3 to (1, 20-dihydroxyvitamin D3 (1,20(OH) 2 D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). Methods and Findings: To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH) 2 D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH) 2 D3 being either equipotent or slightly less potent than 1,25(OH) 2 D3, while 1,20(OH) 2 D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH) 2 D3 was the most potent, 20(OH)D3, 20,23(OH) 2 D3 and 1,20(OH) 2 D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 mg/kg, whereas, 1,20(OH) 2 D3 was slightly to moderately calcemic and 1,25(OH) 2 D3 had strong calcemic activity. Conclusions: We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.

Original languageEnglish (US)
Article numbere9907
JournalPloS one
Volume5
Issue number3
DOIs
StatePublished - Dec 1 2010

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7-dehydrocholesterol
Cholesterol Side-Chain Cleavage Enzyme
cholecalciferol
Cholecalciferol
cytochromes
leukemia
Metabolism
Secosteroids
Leukemia
metabolism
calcitriol
cell differentiation
Ergosterol
cell proliferation
Calcitriol
cells
calcium
therapeutics
20-hydroxyvitamin D3
Rats

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Slominski, A. T., Janjetovic, Z., Fuller, B. E., Zmijewski, M. A., Tuckey, R. C., Nguyen, M. N., ... Holick, M. F. (2010). Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity. PloS one, 5(3), [e9907]. https://doi.org/10.1371/journal.pone.0009907

Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity. / Slominski, Andrzej T.; Janjetovic, Zorica; Fuller, Brian E.; Zmijewski, Michal A.; Tuckey, Robert C.; Nguyen, Minh N.; Sweatman, Trevor; Li, Wei; Zjawiony, Jordan; Miller, Duane; Chen, Tai C.; Lozanski, Gerard; Holick, Michael F.

In: PloS one, Vol. 5, No. 3, e9907, 01.12.2010.

Research output: Contribution to journalArticle

Slominski, AT, Janjetovic, Z, Fuller, BE, Zmijewski, MA, Tuckey, RC, Nguyen, MN, Sweatman, T, Li, W, Zjawiony, J, Miller, D, Chen, TC, Lozanski, G & Holick, MF 2010, 'Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity', PloS one, vol. 5, no. 3, e9907. https://doi.org/10.1371/journal.pone.0009907
Slominski, Andrzej T. ; Janjetovic, Zorica ; Fuller, Brian E. ; Zmijewski, Michal A. ; Tuckey, Robert C. ; Nguyen, Minh N. ; Sweatman, Trevor ; Li, Wei ; Zjawiony, Jordan ; Miller, Duane ; Chen, Tai C. ; Lozanski, Gerard ; Holick, Michael F. / Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity. In: PloS one. 2010 ; Vol. 5, No. 3.
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abstract = "Background: Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH) 2 D3, as well as 1-hydroxyvitamin D3 to (1, 20-dihydroxyvitamin D3 (1,20(OH) 2 D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). Methods and Findings: To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH) 2 D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH) 2 D3 being either equipotent or slightly less potent than 1,25(OH) 2 D3, while 1,20(OH) 2 D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH) 2 D3 was the most potent, 20(OH)D3, 20,23(OH) 2 D3 and 1,20(OH) 2 D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 mg/kg, whereas, 1,20(OH) 2 D3 was slightly to moderately calcemic and 1,25(OH) 2 D3 had strong calcemic activity. Conclusions: We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.",
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T1 - Products of vitamin D3 or 7-dehydrocholesterol metabolism by Cytochrome P450scc show anti- leukemia effects, having low or absent calcemic activity

AU - Slominski, Andrzej T.

AU - Janjetovic, Zorica

AU - Fuller, Brian E.

AU - Zmijewski, Michal A.

AU - Tuckey, Robert C.

AU - Nguyen, Minh N.

AU - Sweatman, Trevor

AU - Li, Wei

AU - Zjawiony, Jordan

AU - Miller, Duane

AU - Chen, Tai C.

AU - Lozanski, Gerard

AU - Holick, Michael F.

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N2 - Background: Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH) 2 D3, as well as 1-hydroxyvitamin D3 to (1, 20-dihydroxyvitamin D3 (1,20(OH) 2 D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). Methods and Findings: To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH) 2 D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH) 2 D3 being either equipotent or slightly less potent than 1,25(OH) 2 D3, while 1,20(OH) 2 D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH) 2 D3 was the most potent, 20(OH)D3, 20,23(OH) 2 D3 and 1,20(OH) 2 D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 mg/kg, whereas, 1,20(OH) 2 D3 was slightly to moderately calcemic and 1,25(OH) 2 D3 had strong calcemic activity. Conclusions: We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.

AB - Background: Cytochrome P450scc metabolizes vitamin D3 to 20-hydroxyvitamin D3 (20(OH)D3) and 20,23(OH) 2 D3, as well as 1-hydroxyvitamin D3 to (1, 20-dihydroxyvitamin D3 (1,20(OH) 2 D3). It also cleaves the side chain of 7-dehydrocholesterol producing 7-dehydropregnenolone (7DHP), which can be transformed to 20(OH)7DHP. UVB induces transformation of the steroidal 5,7-dienes to pregnacalciferol (pD) and a lumisterol-like compounds (pL). Methods and Findings: To define the biological significance of these P450scc-initiated pathways, we tested the effects of their 5,7-diene precursors and secosteroidal products on leukemia cell differentiation and proliferation in comparison to 1α,25-dihydroxyvitamin D3 (1,25(OH) 2 D3). These secosteroids inhibited proliferation and induced erythroid differentiation of K562 human chronic myeloid and MEL mouse leukemia cells with 20(OH)D3 and 20,23(OH) 2 D3 being either equipotent or slightly less potent than 1,25(OH) 2 D3, while 1,20(OH) 2 D3, pD and pL compounds were slightly or moderately less potent. The compounds also inhibited proliferation and induced monocytic differentiation of HL-60 promyelocytic and U937 promonocytic human leukemia cells. Among them 1,25(OH) 2 D3 was the most potent, 20(OH)D3, 20,23(OH) 2 D3 and 1,20(OH) 2 D3 were less active, and pD and pL compounds were the least potent. Since it had been previously proven that secosteroids without the side chain (pD) have no effect on systemic calcium levels we performed additional testing in rats and found that 20(OH)D3 had no calcemic activity at concentration as high as 1 mg/kg, whereas, 1,20(OH) 2 D3 was slightly to moderately calcemic and 1,25(OH) 2 D3 had strong calcemic activity. Conclusions: We identified novel secosteroids that are excellent candidates for anti-leukemia therapy with 20(OH)D3 deserving special attention because of its relatively high potency and lack of calcemic activity.

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