Induction of caspase 3 activity, bcl-2 bax and p65 gene expression modulationin human acute promyelocytic leukemia HL-60 cells by doxorubicin with amifostine.
Journal Title: Pharmacological Reports - Year 2005, Vol 57, Issue 3
Abstract
The influence of amifostine alone and in combination with doxorubicin,cytarabine, and etoposide on the cell growth and on bcl-2, bax and p65 gene expression was investigatedin human acute promyelocytic leukemia cell line HL-60. No or very little influence of the exposure ofHL-60 cells to amifostine (10(-6) to 10(-2) M) on cell proliferation was shown. Proliferation of HL-60cells exposed to doxorubicin, cytarabine, or etoposide dropped down with increasing doses of these drugs.Only in the case of doxorubicin, more effective inhibition of HL-60 cell growth was observed when combinationof doxorubicin, cytarabine or etoposide with amifostine was used. Cytotoxic effect of cytarabine or etoposidewas not reduced by amifostine. The lowering of the cytotoxic index (IC(50)) was observed only when HL-60cells were preincubated with amifostine followed by doxorubicin treatment. IC(50) was estimated as 2.1x 10(-7) M and 0.9 x 10(-7) M for doxorubicin and doxorubicin with amifostine, respectively. This effectwas accompanied by the induction of caspase 3 activity. HL-60 cells treated with doxorubicin alone showedabout 35-fold increase in caspase 3 activity. The enzyme activity was stimulated by combination of doxorubicinwith amifostine up to 94 times. Furthermore, the expression of bcl-2 and bax genes involved in apoptosisas well as tumor-associated p65 gene were determined. Semiquantitative reverse transcriptase polymerasechain reaction showed a decrease in bcl-2 and an increase in bax and p65 expression in HL-60 cells treatedwith doxorubicin in combination with amifostine when compared with the cells treated only with doxorubicin.Amifostine may potentiate doxorubicin therapeutic efficiency in human acute promyelocytic leukemia cells.
Authors and Affiliations
Marek Różalski, Ewa Balcerczak, Urszula Krajewska, Wojciech Młynarski, Ryszard Wierzbicki
Keywords
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