Involvement of reactive oxygen species in aclarubicin-induced differentiation and invasiveness of HL-60 leukemia cells.
Aclarubicin (ACLA), which belongs to the anthracycline class of antineoplastic agents, has been demonstrated as a differentiating agent of human leukemia, including HL-60 cells. We report here on the incidence of ACLA-induced differentiation on matrix metalloproteinase (MMP) expression and cell invasiveness. The aim of this study was to investigate the involvement of reactive oxygen species (ROS) as mediators of ACLA-induced effects. By using a fluorescent probe, we showed that subtoxic (i.e. differentiating) concentration of ACLA generate reactive oxygen species in HL-60 cells. ACLA-differentiated cells exhibited an increased proMMP-9 secretion which has been observed by gelatin zymography and immunoassay. Antioxidants were able to inhibit ACLA-induced differentiation and proMMP-9 secretion. Furthermore, RT-PCR showed that ACLA increased MMP-9 and tissue inhibitor of MMP (TIMP-1) expression in a ROS-dependent manner. In addition, the migration and invasion capacities of HL-60 cells were enhanced by ACLA treatment, but only partially reversed by antioxidants. Altogether, these results evidenced ROS as messengers of ACLA-induced differentiation and MMP-9 expression.
Unité MéDIAN, CNRS FRE-2141, Université de Reims-Champagne Ardenne, Faculté de Pharmacie, F-51096 Reims Cedex, France.
Doriane
D
Richard
Patrick
P
Hollender
Benoît
B
Chénais
D015250:Aclarubicin / Q000494:pharmacology*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D002465:Cell Movement; D017364:Collagenases / Q000235:genetics / Q000378:metabolism; D017931:DNA Primers / Q000737:chemistry; D004792:Enzyme Precursors / Q000235:genetics / Q000378:metabolism; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009361:Neoplasm Invasiveness; D012334:RNA, Neoplasm / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D017931:DNA Primers; D004792:Enzyme Precursors; D012334:RNA, Neoplasm; D017382:Reactive Oxygen Species; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D015250:Aclarubicin; D017364:Collagenases; C120487:pro-matrix metalloproteinase 9; D020780:Matrix Metalloproteinase 9