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See detailEpigenetic Therapy of Lung Cancers: Anti-tumoral effect of valproate on small cell lung cancer
Hubaux, Roland ULg

Doctoral thesis (2011)

Lung cancer is the leading cause of cancer-related death worldwide. Among lung carcinomas, the outcome of small cell lung carcinoma (SCLC) patients is the poorest of any histological subtype with five ... [more ▼]

Lung cancer is the leading cause of cancer-related death worldwide. Among lung carcinomas, the outcome of small cell lung carcinoma (SCLC) patients is the poorest of any histological subtype with five-year survival rate of less than 20 and 5 % for limited and extensive stage respectively. Based on increasing evidence that inhibitors of histones deacetylases (HDAC) have anticancer properties, the goal of this study was to evaluate the ability of valproate (VPA) to improve efficacy of chemotherapeutic regimen in SCLC. We show that VPA directly induces apoptosis of SCLC cell lines at concentrations relevant for clinical uses. Furthermore, VPA synergizes with two chemotherapeutic regimen used in first (cisplatin + etoposide) and second line (cyclophosphamid + vindesine + doxorubicin) treatments. Both mitochondrial and death receptor pathways are involved in VPA-induced apoptosis. Although VPA promotes production of reactive oxygen species, free radical scavenger N-acetylcystein is not sufficient to inhibit apoptosis. As expected, VPA triggers hyperacetylation of histone H3 and increases expression of p21. VPA reduces levels of BclxL, induces cleavage of Bid, translocation of Bax to mitochondria, release of cytochrome c into cytosol and phosphorylation of Erk and H2AX. Transcriptomic analyses by microarrays and quantitative RT-PCR have underscored a series of genes candidates potentially implicated into sensitivity of SCLC to VPA. Among these, the Fzd7 receptor of the WNT pathway is essential for VPA proapoptotic activity. Efficiency of VPA combined to first and second line chemotherapeutic agents is supported by preclinical models of SCLC cells engrafted into SCID mice. The second line combination is presently tested in a clinical trial with patients presenting with refractory or relapsing small cell lung cancer (protocol 01081 at http://www.elcwp.org). [less ▲]

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