Role of CAAT/Enhancer Binding Protein Homologous Protein in Panobinostat-Mediated Potentiation of Bortezomib-Induced Lethal Endoplasmic Reticulum Stress in Mantle Cell Lymphoma Cells
Rekha Rao,Srilatha Nalluri,Warren Fiskus,Andrew Savoie,Kathleen M. Buckley,Kyungsoo Ha,Ramesh Balusu,Atul Joshi,Veena Coothankandaswamy,Jianguo Tao,Eduardo M. Sotomayor,Peter Atadja,Kapil N. Bhalla +12 more
TLDR
It is suggested that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of panobinostat and bortezomib.Abstract:
Purpose: Bortezomib induces unfolded protein response (UPR) and endoplasmic reticulum stress, as well as exhibits clinical activity in patients with relapsed and refractory mantle cell lymphoma (MCL). Here, we determined the molecular basis of the improved in vitro and in vivo activity of the combination of the pan-histone deacetylase inhibitor panobinostat and bortezomib against human, cultured, and primary MCL cells. Experimental Design: Immunoblot analyses, reverse transcription-PCR, and immunofluorescent and electron microscopy were used to determine the effects of panobinostat on bortezomib-induced aggresome formation and endoplasmic reticulum stress in MCL cells. Results: Treatment with panobinostat induced heat shock protein 90 acetylation; depleted the levels of heat shock protein 90 client proteins, cyclin-dependent kinase 4, c-RAF, and AKT; and abrogated bortezomib-induced aggresome formation in MCL cells. Panobinostat also induced lethal UPR, associated with induction of CAAT/enhancer binding protein homologous protein (CHOP). Conversely, knockdown of CHOP attenuated panobinostat-induced cell death of MCL cells. Compared with each agent alone, cotreatment with panobinostat increased bortezomib-induced expression of CHOP and NOXA, as well as increased bortezomib-induced UPR and apoptosis of cultured and primary MCL cells. Cotreatment with panobinostat also increased bortezomib-mediated in vivo tumor growth inhibition and improved survival of mice bearing human Z138C MCL cell xenograft. Conclusion: These findings suggest that increased UPR and induction of CHOP are involved in enhanced anti-MCL activity of the combination of panobinostat and bortezomib. Clin Cancer Res; 16(19); 4742–54. ©2010 AACR.read more
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Preclinical activity, pharmacodynamic, and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma
Loredana Santo,Teru Hideshima,Andrew L. Kung,Jen-Chieh Tseng,David Tamang,Min Yang,Matthew Jarpe,John H. Van Duzer,Ralph Mazitschek,Walter Ogier,Diana Cirstea,Scott J. Rodig,Homare Eda,Tyler Scullen,Miriam Canavese,James E. Bradner,Kenneth C. Anderson,Simon S. Jones,Noopur Raje +18 more
TL;DR: In vivo and preclinical studies provide preclinical rationale for acetylated α-tubulin use as a pharmacodynamic biomarker in future clinical trials for HDAC6 inhibition in multiple myeloma.
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Histone deacetylase inhibitor (HDACI) mechanisms of action: emerging insights.
TL;DR: This review focuses on relatively recently identified mechanisms of action of HDACI, with particular emphasis on those that relate to the DNA damage response (DDR), and discusses synergistic strategies combining HDACIs with several novel targeted agents that disrupt the DDR or antagonize anti-apoptotic proteins that could have implications for the future use ofHDACIs in patients with cancer.
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Auranofin Induces Lethal Oxidative and Endoplasmic Reticulum Stress and Exerts Potent Preclinical Activity against Chronic Lymphocytic Leukemia
Warren Fiskus,Nakhle S. Saba,Min Shen,Mondana H. Ghias,Jinyun Liu,Soumyasri Das Gupta,Lata Chauhan,Rekha Rao,Sumedha Gunewardena,Kevin Schorno,Christopher P. Austin,Kami J. Maddocks,John C. Byrd,Ari Melnick,Peng Huang,Adrian Wiestner,Kapil N. Bhalla +16 more
TL;DR: The identification of an existing U.S. Food and Drug Administration-approved small-molecule drug to repurpose for CLL treatment is reported and results provide a rationale to reposition the approved drug auranofin for clinical evaluation in the therapy of CLL.
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Combination of Pan-Histone Deacetylase Inhibitor and Autophagy Inhibitor Exerts Superior Efficacy against Triple-Negative Human Breast Cancer Cells
Rekha Rao,Ramesh Balusu,Warren Fiskus,Uma Mudunuru,Sreedhar Venkannagari,Lata Chauhan,Jacqueline E. Smith,Stacey Hembruff,Kyungsoo Ha,Peter Atadja,Kapil N. Bhalla +10 more
TL;DR: Cotreatment with an autophagy inhibitor and pan-HDI, for example, chloroquine and panobinostat results in accumulation of toxic polyubiquitylated proteins, exerts superior inhibitory effects on TNBC cell growth, and increases the survival of TNBC xenografts.
References
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CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum
Stefan J. Marciniak,Chi Yun,Seiichi Oyadomari,Isabel Novoa,Yuhong Zhang,Rivka Jungreis,Kazuhiro Nagata,Heather P. Harding,David Ron +8 more
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