The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
[en] 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 activityin -
volved in cancer cell growth and survival pathways.
We examined the efficacyof 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
<25 nmol/L. In lung cancer and mesothelioma animal
models, panobinostat significantlyde creased tumor
growth byan average of 62% when compared with vehicle
control. Panobinostat was equallye ffective in
immunocompetent and severe combined immunodeficiencymic
e, indicating that the inhibition of tumor growth by
panobinostat was not due to direct immunologic effects.Panobinostat was, however, particularlyeffective in SCLC
xenografts, and the addition of the chemotherapyag ent
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 maybe a useful adjunct in the
treatment of thoracic malignancies, especiallySCLC.
Disciplines :
Oncology
Author, co-author :
Crisanti, Cecilia
Wallace, Africa
Kapoor, Veena
Vandermeers, Fabian ; Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Dowling, Melissa
Pereira, Luana
Coleman, Kara
Campling, Barbara
Fridlender, Zvi
Kao, Gary
Albelda, Steven
Language :
English
Title :
The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer
Publication date :
August 2009
Journal title :
Molecular Cancer Therapeutics
ISSN :
1535-7163
eISSN :
1538-8514
Publisher :
American Association for Cancer Research, Inc. (AACR), Philadelphia, United States - Pennsylvania
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