The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage

Rentian Feng, Ana Oton, Markus Y. Mapara, Gülsüm Anderson, Chandra Belani, Suzanne Lentzsch

Research output: Contribution to journalArticle

98 Citations (Scopus)

Abstract

Clinical trials have shown the high anti-myeloma activity of the proteasome inhibitor bortezomib. The present study examined the activity of bortezomib combined with PXD101, a histone deacetylase inhibitor, against multiple myeloma (MM) and osteoclastogenesis. Treatment of myeloma cell lines with combinations of bortezomib and PXD101 led to synergistic inhibition of proliferation and induction of cell death. The combination significantly decreased the viability of primary human CD138+ myeloma cells but not of bone marrow mononuclear cells. Further studies showed a dose-dependent activation of caspases-3, -8 and -9 and nuclear fragmentation in myeloma cells. Bortezomib/PXD101 treatment markedly triggered reactive oxygen species (ROS) generation that was accompanied by p53, H2A.X and p38-mitogen-activated protein kinase phosphorylation. ROS generation could be blocked by the free radical scavenger N-acetyl-l-cysteine. The combination of bortezomib and PXD101 also resulted in synergistic inhibition of osteoclast formation. In conclusion, bortezomib and PXD101 have different molecular targets. The combination induces cell death in myeloma cells via ROS-mediated DNA damage and also inhibits osteoclastogenesis. Therefore, this study provides the rationale for the clinical evaluation of bortezomib combined with PXD101 in patients with MM.

Original languageEnglish (US)
Pages (from-to)385-397
Number of pages13
JournalBritish Journal of Haematology
Volume139
Issue number3
DOIs
StatePublished - Nov 1 2007

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Histone Deacetylase Inhibitors
Multiple Myeloma
DNA Damage
Oxidative Stress
Reactive Oxygen Species
Osteogenesis
Cell Death
Free Radical Scavengers
Proteasome Inhibitors
Caspase 8
p38 Mitogen-Activated Protein Kinases
Osteoclasts
Bortezomib
belinostat
Caspase 3
Bone Marrow Cells
Cysteine
Phosphorylation
Clinical Trials
Cell Line

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

Feng, Rentian ; Oton, Ana ; Mapara, Markus Y. ; Anderson, Gülsüm ; Belani, Chandra ; Lentzsch, Suzanne. / The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. In: British Journal of Haematology. 2007 ; Vol. 139, No. 3. pp. 385-397.
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The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage. / Feng, Rentian; Oton, Ana; Mapara, Markus Y.; Anderson, Gülsüm; Belani, Chandra; Lentzsch, Suzanne.

In: British Journal of Haematology, Vol. 139, No. 3, 01.11.2007, p. 385-397.

Research output: Contribution to journalArticle

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