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. IC(50) and LD(50) 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 LD(50) values consistently <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-X(L). These studies together suggest that
panobinostat may be a useful adjunct in the treatment of thoracic
malignancies, especially SCLC.