Products of vitamin D3 or 7-dehydrocholesterol metabolism by cytochrome P450scc show anti-leukemia effects, having low or absent calcemic activity.
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 1alpha,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).


RESULTS
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 1alpha,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 microg/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.
Slominski
Andrzej T
AT
Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, Tennessee, United States of America. aslominski@uthsc.edu
Janjetovic
Zorica
Z
Fuller
Brian E
BE
Zmijewski
Michal A
MA
Tuckey
Robert C
RC
Nguyen
Minh N
MN
Sweatman
Trevor
T
Li
Wei
W
Zjawiony
Jordan
J
Miller
Duane
D
Chen
Tai C
TC
Lozanski
Gerard
G
Holick
Michael F
MF
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002762:Cholecalciferol / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000378:metabolism*; D003684:Dehydrocholesterols / Q000737:chemistry / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D018922:HL-60 Cells; D006801:Humans; D006934:Hypercalcemia / Q000378:metabolism*; D051379:Mice; D011284:Pregnenolone / Q000031:analogs & derivatives / Q000737:chemistry; D020298:U937 Cells
C480634:20-hydroxyvitamin D3; C480635:7-dehydropregnenolone; D000970:Antineoplastic Agents; D003684:Dehydrocholesterols; D002762:Cholecalciferol; D011284:Pregnenolone; C016705:7-dehydrocholesterol; D002786:Cholesterol Side-Chain Cleavage Enzyme; D002112:Calcifediol