Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells
Joint Authors
Watkins, D. Neil
Marini, Kieren D.
Irving, Aaron T.
Rossello, Fernando J.
Kansara, Maya
Jayasekara, W. Samantha N.
Thomas, David M.
McCaw, Andrew
Ashley, David M.
Cain, Jason E.
Source
Issue
Vol. 2013, Issue 2013 (31 Dec. 2013), pp.1-11, 11 p.
Publisher
Hindawi Publishing Corporation
Publication Date
2013-02-28
Country of Publication
Egypt
No. of Pages
11
Main Subjects
Abstract EN
Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation.
However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents.
In many cases, HDACi doses necessary to induce these effects result in significant toxicity.
Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit.
Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death.
Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers.
In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression.
These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity.
American Psychological Association (APA)
Cain, Jason E.& McCaw, Andrew& Jayasekara, W. Samantha N.& Rossello, Fernando J.& Marini, Kieren D.& Irving, Aaron T.…[et al.]. 2013. Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells. Complexity،Vol. 2013, no. 2013, pp.1-11.
https://search.emarefa.net/detail/BIM-1011461
Modern Language Association (MLA)
Cain, Jason E.…[et al.]. Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells. Complexity No. 2013 (2013), pp.1-11.
https://search.emarefa.net/detail/BIM-1011461
American Medical Association (AMA)
Cain, Jason E.& McCaw, Andrew& Jayasekara, W. Samantha N.& Rossello, Fernando J.& Marini, Kieren D.& Irving, Aaron T.…[et al.]. Sustained Low-Dose Treatment with the Histone Deacetylase Inhibitor LBH589 Induces Terminal Differentiation of Osteosarcoma Cells. Complexity. 2013. Vol. 2013, no. 2013, pp.1-11.
https://search.emarefa.net/detail/BIM-1011461
Data Type
Journal Articles
Language
English
Notes
Includes bibliographical references
Record ID
BIM-1011461