The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cellsin vitroandin vivowith particular efficacy for small cell lung cancer

Abstract

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 <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.

Combinations of DNA Methyltransferase and Histone Deacetylase Inhibitors Induce DNA Damage in Small Cell Lung Cancer Cells: Correlation of Resistance with IFN-Stimulated Gene Expression

“…Cell cycle analysis showed an increase in sub-G 0 population and G 2 -M arrest in sensitive cell lines after treatment with HDAC inhibitors alone or in combination with 5-AZA-dC. Accumulation of cells in G 2 -M phase after treatment of SCLC cells with either LBH589 alone or in combination with etoposide has also been reported (38). Longer exposure (60 h) to the HDAC inhibitor resulted in the increase of dead cells.…”

“…Longer exposure (60 h) to the HDAC inhibitor resulted in the increase of dead cells. In the latter case, LBH589 was potent not only in cell lines but in tumor xenografts as well (38).…”

Research Priorities for Endometriosis: Recommendations From a Global Consortium of Investigators in Endometriosis

“…52,53 During the last decade, many drugs with histone deacetylase (HDAC)-inhibiting action have been shown to induce growth arrest, apoptosis, and differentiation of tumor cells. 54,55 It was recently shown that different types of lesions vary in the expression of HDACs 56,57 and that tissues (lesions and endometrium) from patients have different levels of H3K9 and H4K16 acetylation compared to control tissues. 58,59 Thus, evidence has started to accumulate that endometriotic lesions have a characteristic histone code and that global H3 and H4 acetylation within promoter regions of candidate genes is differentially modulated in lesions.…”

Three-Dimensional Cell Growth Confers Radioresistance by Chromatin Density Modification

“…Preclinical and clinical evaluation of the potential of HDACs as cancer targets using pharmacologic inhibitors showed cytotoxic effects in hematopoietic malignancies and cytostatic effects in cells from solid tumors (11,(13)(14)(15). Based on the function of HDACs in chromatin organization and gene expression, HDAC inhibitors, such as the HDAC class I/II inhibitor LBH589 (Panobinostat), have successfully been tested as radiosensitizing agents (16)(17)(18)(19)(20).…”