Article (Scientific journals)
Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy
Hubaux, Roland; Vandermeers, Fabian; Crisanti, Cecilia et al.
2010In European Journal of Cancer, 46, p. 1724-1734
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Keywords :
Small cell lung cancer; Valproate; HDAC; Chemotherapy; Mice
Abstract :
[en] 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 18 kDa 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.
Disciplines :
Author, co-author :
Hubaux, Roland
Vandermeers, Fabian ;  Université de Liège - ULiège > Département des sciences cliniques > Labo de biologie des tumeurs et du développement
Crisanti, Cecilia
Kapoor, Veena
Burny, Arsène ;  Université de Liège - ULiège > Agro Biotech Gembloux
Mascaux, Céline
Albelda, Steven M.
Willems, Luc  ;  Université de Liège - ULiège > Chimie et bio-industries > Centre de Bio. Fond. - Section de Biologie cell. et moléc.
Language :
Title :
Preclinical evidence for a beneficial impact of valproate on the response of small cell lung cancer to first-line chemotherapy
Publication date :
09 June 2010
Journal title :
European Journal of Cancer
Publisher :
Elsevier Science, Oxford, United Kingdom
Volume :
Pages :
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 30 November 2010


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