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Mechanisms of resistance to the cytotoxic effects of oxysterols in human leukemic cells

Gregorio-King, Claudia C., Gough, Tamara, Van Der Meer, Gavin J., Hosking, Jane B., Waugh, Caryll M., McLeod, Janet L., Collier, Fiona Mc and Kirkland, Mark A. 2004, Mechanisms of resistance to the cytotoxic effects of oxysterols in human leukemic cells, Journal of steroid biochemistry and molecular biology, vol. 88, no. 3, pp. 311-320, doi: 10.1016/j.jsbmb.2003.12.007.

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Title Mechanisms of resistance to the cytotoxic effects of oxysterols in human leukemic cells
Author(s) Gregorio-King, Claudia C.
Gough, Tamara
Van Der Meer, Gavin J.
Hosking, Jane B.
Waugh, Caryll M.
McLeod, Janet L.
Collier, Fiona Mc
Kirkland, Mark A.
Journal name Journal of steroid biochemistry and molecular biology
Volume number 88
Issue number 3
Start page 311
End page 320
Total pages 10
Publisher Pergamon
Place of publication Kidlington, England
Publication date 2004-03
ISSN 0960-0760
Summary We have developed hematopoietic cells resistant to the cytotoxic effects of oxysterols. Oxysterol-resistant HL60 cells were generated by continuous exposure to three different oxysterols—25-hydroxycholesterol (25-OHC), 7-beta-hydroxycholesterol (7β-OHC) and 7-keto-cholesterol (7κ-C). We investigated the effects of 25-OHC, 7β-OHC, 7κ-C and the apoptotic agent staurosporine on these cells. The effect of the calcium channel blocker nifedipine on oxysterol cytotoxicity was also investigated. Differential display and real-time PCR were used to quantitate gene expression of oxysterol-sensitive and -resistant cells. Our results demonstrate that resistance to the cytotoxic effects of oxysterols is relatively specific to the type of oxysterol, and that the cytotoxicity of 25-OHC but not that of 7β-OHC and 7κ-C, appears to occur by a calcium dependent mechanism. Oxysterol-resistant cells demonstrated no significant difference in the expression of several genes previously implicated in oxysterol resistance, but expressed the bcl-2 gene at significantly lower levels than those observed in control cells. We identified three novel genes differentially expressed in resistant cells when compared to HL60 control cells. Taken together, the results of this study reveal potentially novel mechanisms of oxysterol cytotoxicity and resistance, and indicate that cytotoxicity of 25-OHC, 7β-OHC and 7κ-C occur by independent, yet overlapping mechanisms.
Language eng
DOI 10.1016/j.jsbmb.2003.12.007
Field of Research 110107 Metabolic Medicine
Socio Economic Objective 970111
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2004, Elsevier
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Document type: Journal Article
Collection: School of Medicine
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