This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Maiso, P. Articles by San Miguel, J. F. Search for Related Content PubMed PubMed Citation Articles by Maiso, P. Articles by San Miguel, J. F.

The Histone Deacetylase Inhibitor LBH589 Is a Potent Antimyeloma Agent that Overcomes Drug Resistance

¹ Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Cientificas, Universidad de Salamanca; ² Hospital Universitario de Salamanca, Salamanca, Spain; and ³ Novartis Pharmaceuticals, East Hanover, New Jersey

Requests for reprints: Atanasio Pandiella, Centro de Investigación del Cáncer, Universitad de Salamanca, Campus Miguel de Unamuno, 37007 Salamanca, Spain. Phone: 34-923-294815; E-mail: atanasio{at}usal.es.

Multiple myeloma represents an incurable disease, for which development of new therapies is required. Here, we report the effect on myeloma cells of LBH589, a new hydroxamic acid–derived histone deacetylase inhibitor. LBH589 was a potent antimyeloma agent (IC₅₀ < 40 nmol/L) on both cell lines and fresh cells from multiple myeloma patients, including cells resistant to conventional chemotherapeutic agents. In addition, LBH589 potentiated the action of drugs, such as bortezomib, dexamethasone, or melphalan. Using gene array, quantitative PCR, and Western analyses, we observed that LBH589 affected a large number of genes involved in cell cycle and cell death pathways. LBH589 blocked cell cycle progression, and this was accompanied by p21, p53, and p57 up-regulation. LBH589 induced cell death through an increase in the mitochondrial outer membrane permeability. LBH589 favored apoptosome formation by inducing cytochrome c release, Apaf-1 up-regulation, and caspase-9 cleavage. In addition, LBH589 stimulated a caspase-independent pathway through the release of AIF from the mitochondria. LBH589 down-regulated Bcl-2 and particularly Bcl-X. Moreover, overexpression of Bcl-X in multiple myeloma cells prevented LBH589-induced cell death. All these data indicate that LBH589 could be a useful drug for the treatment of multiple myeloma patients. (Cancer Res 2006; 66(11): 5781-9)

This article has been cited by other articles:

				L. Ellis, Y. Pan, G. K. Smyth, D. J. George, C. McCormack, R. Williams-Truax, M. Mita, J. Beck, H. Burris, G. Ryan, et al. Histone Deacetylase Inhibitor Panobinostat Induces Clinical Responses with Associated Alterations in Gene Expression Profiles in Cutaneous T-Cell Lymphoma Clin. Cancer Res., July 15, 2008; 14(14): 4500 - 4510. [Abstract] [Full Text] [PDF]

				C. S. Mitsiades, E. M. Ocio, A. Pandiella, P. Maiso, C. Gajate, M. Garayoa, D. Vilanova, J. C. Montero, N. Mitsiades, C. J. McMullan, et al. Aplidin, a Marine Organism-Derived Compound with Potent Antimyeloma Activity In vitro and In vivo Cancer Res., July 1, 2008; 68(13): 5216 - 5225. [Abstract] [Full Text] [PDF]

				J. C. Montero, R. Lopez-Perez, J. F. San Miguel, and A. Pandiella Expression of c-Kit isoforms in multiple myeloma: differences in signaling and drug sensitivity Haematologica, June 1, 2008; 93(6): 851 - 859. [Abstract] [Full Text] [PDF]

				E. De Bruyne, T. J. Bos, K. Asosingh, I. Vande Broek, E. Menu, E. Van Valckenborgh, P. Atadja, V. Coiteux, X. Leleu, K. Thielemans, et al. Epigenetic Silencing of the Tetraspanin CD9 during Disease Progression in Multiple Myeloma Cells and Correlation with Survival Clin. Cancer Res., May 15, 2008; 14(10): 2918 - 2926. [Abstract] [Full Text] [PDF]

				A. Scuto, M. Kirschbaum, C. Kowolik, L. Kretzner, A. Juhasz, P. Atadja, V. Pullarkat, R. Bhatia, S. Forman, Y. Yen, et al. The novel histone deacetylase inhibitor, LBH589, induces expression of DNA damage response genes and apoptosis in Ph- acute lymphoblastic leukemia cells Blood, May 15, 2008; 111(10): 5093 - 5100. [Abstract] [Full Text] [PDF]

				Q. Zhou, A. T. Agoston, P. Atadja, W. G. Nelson, and N. E. Davidson Inhibition of Histone Deacetylases Promotes Ubiquitin-Dependent Proteasomal Degradation of DNA Methyltransferase 1 in Human Breast Cancer Cells Mol. Cancer Res., May 1, 2008; 6(5): 873 - 883. [Abstract] [Full Text] [PDF]

				V. R. Fantin and V. M. Richon Mechanisms of Resistance to Histone Deacetylase Inhibitors and Their Therapeutic Implications Clin. Cancer Res., December 15, 2007; 13(24): 7237 - 7242. [Abstract] [Full Text] [PDF]

				A. Edwards, J. Li, P. Atadja, K. Bhalla, and E. B. Haura Effect of the histone deacetylase inhibitor LBH589 against epidermal growth factor receptor dependent human lung cancer cells Mol. Cancer Ther., September 1, 2007; 6(9): 2515 - 2524. [Abstract] [Full Text] [PDF]