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Blood, 23 April 2009, Vol. 113, No. 17, pp. 4038-4048. Prepublished online as a Blood First Edition Paper on December 12, 2008; DOI 10.1182/blood-2008-08-176024. This Article Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-08-176024v1 113/17/4038    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Chen, J. Articles by Bhalla, K. N. Search for Related Content PubMed PubMed Citation Articles by Chen, J. Articles by Bhalla, K. N. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted August 27, 2008 Accepted November 28, 2008 Co-treatment with BCL-2 antagonist sensitizes cutaneous T cell lymphoma to lethal action of HDAC7-Nur77 based mechanism Jianguang Chen, Warren Fiskus, Kelly Eaton, Pravina Fernandez, Yongchao Wang, Rekha Rao, Pearl Lee, Rajeshree Joshi, Yonghua Yang, Ravindra Kolhe, Ramesh Balusu, Prasanthi Chappa, Kavita Natarajan, Anand Jillella, Peter Atadja, and Kapil N. Bhalla* Medical College of Georgia Cancer Center, Augusta, GA, United States Novartis Institute for Biomedical Research Inc., Cambridge, MA, United States * Corresponding author; email: kbhalla{at}mcg.edu. Pan-histone deacetylase inhibitors, e.g., vorinostat and panobinostat (LBH589, Novartis Pharmaceuticals) have shown clinical efficacy against advanced cutaneous T-cell lymphoma (CTCL). However, the molecular basis of this activity remains unclear. HDAC7, a class IIA histone deacetylase (HDAC), is overexpressed in thymocytes, where it represses expression of the proapoptotic nuclear orphan receptor Nur77. Here, we demonstrate that treatment with panobinostat rapidly inhibits the in vitro and intracellular activity, as well as the mRNA and protein levels of HDAC7 and induces expression and translocation of Nur77 to the mitochondria. There, Nur77 converts death resistance protein Bcl-2 into a killer protein, promoting cell death of cultured and patient-derived human CTCL cells. Treatment with panobinostat improved survival of athymic nude mice implanted with human CTCL cells. Ectopic expression of Nur77 induced apoptosis and sensitized HH cells to panobinostat, while combined knockdown of Nur77 and its family member Nor1 was necessary to inhibit panobinostat-induced apoptosis of CTCL cells. Co-treatment with the Bcl-2/Bcl-xL antagonist ABT-737 decreased resistance and synergistically induced apoptosis of human CTCL cells. These findings mechanistically implicate HDAC7 and Nur77 in sensitizing human CTCL cells to panobinostat as well as suggest that co-treatment with an anti-Bcl-2 agent would augment the anti-CTCL activity of panobinostat. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: W. Fiskus, Y. Wang, A. Sreekumar, K. M. Buckley, H. Shi, A. Jillella, C. Ustun, R. Rao, P. Fernandez, J. Chen, et al. Combined epigenetic therapy with the histone methyltransferase EZH2 inhibitor 3-deazaneplanocin A and the histone deacetylase inhibitor panobinostat against human AML cells Blood, September 24, 2009; 114(13): 2733 - 2743. [Abstract] [Full Text] [PDF]

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