RT Journal Article
SR Electronic
T1 The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells <em>in vitro</em> and <em>in vivo</em> with particular efficacy for small cell lung cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP 2221
OP 2231
DO 10.1158/1535-7163.MCT-09-0138
VO 8
IS 8
A1 Crisanti, M. Cecilia
A1 Wallace, Africa F.
A1 Kapoor, Veena
A1 Vandermeers, Fabian
A1 Dowling, Melissa L.
A1 Pereira, Luana P.
A1 Coleman, Kara
A1 Campling, Barbara G.
A1 Fridlender, Zvi G.
A1 Kao, Gary D.
A1 Albelda, Steven M.
YR 2009
UL http://mct.aacrjournals.org/content/8/8/2221.abstract
AB Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC50 and LD50 values were in the low nmol/L range (4–470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD50 values consistently &lt;25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-XL. These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC. [Mol Cancer Ther 2009;8(8):2221–31]