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.
Hubaux
Roland
R
Cellular and Molecular Biology, Gembloux Agro-Bio Tech, Gembloux, Belgium.
Vandermeers
Fabian
F
Crisanti
M Cecilia
MC
Crisanti
Cecilia
C
Kapoor
Veena
V
Burny
Arsène
A
Mascaux
Céline
C
Albelda
Steven M
SM
Willems
Luc
L
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D004357:Drug Synergism; D005047:Etoposide / Q000008:administration & dosage; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D046228:Microarray Analysis; D009368:Neoplasm Transplantation; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy*; D014183:Transplantation, Heterologous; D014635:Valproic Acid / Q000627:therapeutic use*
D056572:Histone Deacetylase Inhibitors; D014635:Valproic Acid; D005047:Etoposide; D020169:Caspases; D002945:Cisplatin