The histone deacetylase inhibitor, PXD101, potentiates bortezomib-induced anti-multiple myeloma effect by induction of oxidative stress and DNA damage.
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.
Feng
Rentian
R
Division of Hematology/Oncology, Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15232, USA.
Oton
Ana
A
Mapara
Markus Y
MY
Anderson
Gülsüm
G
Belani
Chandra
C
Lentzsch
Suzanne
S
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001854:Bone Marrow Cells / Q000187:drug effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009363:Neoplasm Proteins / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013449:Sulfonamides
D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D001897:Boronic Acids; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D011719:Pyrazines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D000069286:Bortezomib; C487081:belinostat