The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer

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

Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy.

Prognosis of small cell lung carcinoma (SCLC) is particularly poor, less than 5% of patients with extensive stage being alive after two years. We hypothesized that SCLC chemotherapy could be improved by using histone deacetylase (HDAC) inhibitors based on their ability to interfere with lysine acetylation and to alter gene expression. The goal of this study was to evaluate the anticancer efficacy of a HDAC inhibitor (valproate: VPA) on SCLC cells in combination with the standard chemotherapeutic first-line regimen (cisplatin+etoposide). We show that VPA induces apoptosis of small cell lung cancer cell lines and improves efficacy of cisplatin combined with etoposide. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. As expected for an HDAC inhibitor, VPA hyperacetylates histone H3. The mechanism of VPA pro-apoptotic activity involves induction of p21, inhibition of Bcl-xL, cleavage of Bid and phosphorylation of Erk and H2AX. In the presence of VPA, Bax is translocated from the cytoplasm to the mitochondria and cleaved in an 18kDa isoform. Cytochrome c is released from the mitochondria into the cytosol. Transcriptomic analyses by microarray show that VPA modulates transcription of genes (Na(+)/K(+) ATPase, Bcl-xL) involved in chemoresistance to cisplatin and etoposide. Finally, the efficacy of VPA combined with cisplatin and etoposide is supported by preclinical models of SCLC cells engrafted into SCID mice. Together, these data demonstrate that VPA augments anticancer activity of cisplatin and etoposide, two components of the standard first-line chemotherapy of small cell lung cancer.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Erratum: Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy (European Journal of Cancer (2010) 46:9 (1724-1734))

SCOPUS: er.jinfo:eu-repo/semantics/publishe

Valproic acid improves second-line regimen of small cell lung carcinoma in preclinical models

With 5-year survival rates below 5%, small cell lung carcinoma (SCLC) has very poor prognosis and requires improved therapies. Despite an excellent overall response to first-line therapy, relapses are frequent and further treatments are disappointing. The goal of the study was to improve secondline therapy of SCLC. The effect of chemotherapeutic agents was evaluated in cell lines (apoptosis, reactive oxygen species, and RNA and protein expression) and in mouse models (tumour development). We demonstrate here that valproic acid, a histone deacetylase inhibitor, improves the efficacy of a second-line regimen (vindesine, doxorubicin and cyclophosphamide) in SCLC cells and in mouse models. Transcriptomic profiling integrating microRNA and mRNA data identifies key signalling pathways in the response of SCLC cells to valproic acid, opening new prospects for improved therapies