Possible role of cholesterol in the susceptibility of a human acute lymphoblastic leukemia cell line to dexamethasone.
Because the absence of high affinity glucocorticoid receptors in lymphoid leukemia cells does not always correlate with the resistance to glucocorticoids in vitro, an effort was made to identify an alternate biochemical marker which, independently from the receptor system, would improve the reliability of the existing in vitro sensitivity assays as predictors of the patients' response to glucocorticoid therapy. Two receptor-containing lines of acute lymphoblastic leukemia, one glucocorticoid sensitive (CEM-C7) and one glucocorticoid resistant (CEM-C1), were used to study endogenous synthesis of cholesterol with [14C]-acetate as a cholesterol precursor. We found that dexamethasone inhibited cholesterol synthesis in the glucocorticoid-sensitive clone but was without effect on the resistant clone. In sensitive cells, this reduction in synthesis was paralleled by a decreased activity of 3-hydroxy-3-methylglutaryl coenzyme A synthase (EC 1.1.3.5) and was followed by a moderate decrease in cellular free cholesterol. Moreover, sonic dispersions of cholesterol in delipidized serum when added to the cultures reversed the growth-inhibitory effect of dexamethasone on CEM-C7 cells.
Madden
E A
EA
Bishop
E J
EJ
Fiskin
A M
AM
Melnykovych
G
G
D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000502:physiology*; D003907:Dexamethasone / Q000494:pharmacology*; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000378:metabolism; D007945:Leukemia, Lymphoid / Q000473:pathology / Q000503:physiopathology*; D008148:Lovastatin / Q000031:analogs & derivatives*; D009281:Naphthalenes / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000096:biosynthesis; D013997:Time Factors
D009281:Naphthalenes; D009363:Neoplasm Proteins; C012258:mevastatin; D003907:Dexamethasone; D002784:Cholesterol; D008148:Lovastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D006904:Hydroxymethylglutaryl-CoA Synthase