5/12/13 Panobinostat, a Novel Histone Deacetylase (HiDAC) Inhibitor Enhances the Anti-Tumor Activity of Bortezomib (BTZ) In Rituximab-Chemotherapy ...
5/12/13
Panobinostat, a Novel Histone Deacetylase (HiDAC) Inhibitor Enhances the Anti-Tumor Activity of Bortezomib (BTZ) In Rituximab-Chemotherapy Sensitive a…
SEA RCH:
Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 3936 © 2010 American Society of Hematology
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Oral Session Lymphoma - Pre-Clinical - Chemotherapy and Biologic Agents: Poster II
Panobinostat, a Novel Histone Deacetylase (HiDAC) Inhibitor Enhances the AntiTumor Activity of Bortezomib (BTZ) In Rituximab-Chemotherapy Sensitive and Resistant Lymphoma Cell Lines Francisco J. Hernandez-Ilizaliturri, MD1 , Cory Mavis, BSc, MSc*,1 , Ilir Maraj*,2 , Mohammad Muhsin Chisti*,3 , John Gibbs, MD*,4 and Myron S. Czuczman, MD1 1 Departments of Immunology and Medicine, Roswell Park Cancer Institute,
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Buffalo, NY, USA, 2 Internal Medicine, SUNY Down State Medical Center, Brooklyn, NY, 3 Beaumont Cancer Center, Royal Oak, MI, USA, 4 Surgical Oncology, Roswell Park Cancer Institute, Buffalo, NY, USA
Abstract 3936 Deacetylases (DACs) are enzymes that remove the acetyl groups from target proteins [histones (class I) and nonhistone proteins (class II)], leading to regulation of gene transcription and other cellular processes. Panobinostat (LBH589) is a novel and potent DAC class I and II inhibitor undergoing pre-clinical and clinical testing. In order to better characterize the role of DAC inhibitors in the treatment of refractory/resistant B-cell lymphoma., We studied the anti-tumor activity of panobinostat as a single agent or in combination with the proteasome inhibitor (BTZ) against a panel of rituximab-[chemotherapy]-sensitive cell lines (RSCL), rituximab-[chemotherapy]-resistant cell lines (RRCL), and primary lymphoma cells isolated from patients with treatment-naïve or refractory/relapsed B-cell lymphoma. In addition, we characterized the mechanisms responsible for panobinostat anti-tumor activity. NonHodgkin lymphoma (NHL) cell lines were exposed to escalating doses of panobinostat (0.5-5nM) +/– BTZ (15nM). Changes in mitochondrial potential and ATP synthesis were determined by alamar blue reduction and cell titer glo luminescent assays, respectively. Subsequently, protein lysates were isolated from panobinostat +/– BTZ exposed cells and changes in members of Bcl-2 family proteins were evaluated by Western blot. Finally, to characterize panobinostat's mechanisms-of-action, lymphoma cells were exposed to panobinostat with or without pan-caspase (Q-VD-OPh, 5mM) or autophagy (3-methyladenine [3MA] 5mM) inhibitors and changes in cell viability were detected as above. Optimal experimental conditions were confirmed by Western blot. Panobinostat exhibited dose-dependent activity as a single agent against RSCL, RRCL and patient-derived primary tumor cells (N=25). In addition, synergistic activity was observed by combining panobinostat with BTZ in vitro. The pharmacological interactions between panobinostat and proteasome inhibitor could be explained in part by the effects each agent has on the expression levels of Bcl-2 family members. In vitro exposure of lymphoma cells to panobinostat resulted in Bcl-XL down-regulation, whereas BTZ exposure causes up-regulation of Bak and Noxa and downregulation of Mcl-1 and Bcl-XL. Caspase inhibition diminished panobinostat anti-tumor activity in RSCL but not in RRCL. On the other hand, exposure of RRCL to 3MA, significantly inhibited the anti-tumor activity of panobinostat in RRCL. Together this data suggest that, panobinostat has a dual mechanism-of-action and can induce cell death by caspase-dependent and -independent pathways. Our data suggests that panobinostat as a single agent is active against rituximab-chemotherapy sensitive and resistant lymphoma cells and potentiates the anti-tumor activity of a proteasome inhibitor (BTZ). A better understanding in the molecular events (caspase-dependent and independent) triggered by panobinostat in combination with proteasome inhibition is important in order to develop abstracts.hematologylibrary.org/cgi/content/abstract/116/21/3936?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=chisti&searchid=1&FIRSTINDEX=0&so…
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5/12/13
Panobinostat, a Novel Histone Deacetylase (HiDAC) Inhibitor Enhances the Anti-Tumor Activity of Bortezomib (BTZ) In Rituximab-Chemotherapy Sensitive a…
independent) triggered by panobinostat in combination with proteasome inhibition is important in order to develop optimal combination strategies using these exciting agents in future clinical trials. (Research, in part, supported by a NIH grant R01 CA136907-01A1 awarded to Roswell Park Cancer Institute) Disclosures: No relevant conflicts of interest to declare.
Footnotes *
Asterisk with author names denotes non-ASH members.
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Online ISSN: 1528-0020
abstracts.hematologylibrary.org/cgi/content/abstract/116/21/3936?maxtoshow=&hits=10&RESULTFORMAT=&fulltext=chisti&searchid=1&FIRSTINDEX=0&so…
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