Abstract
Abstract Based on the ability of histone deacetylase inhibitors to modulate the expression of genes relevant for growth regulatory or apoptotic pathways, the purpose of the present study was to explore the interest of novel combination treatments for drug-resistant tumors. Thus, using cellular and biochemical pharmacology approaches, we examined the effect of the combination between the novel histone deacetylase inhibitor ST2782 and the proteasome inhibitor bortezomib in ovarian carcinoma cell lines, including the parental IGROV-1 cell line and two platinum-resistant sublines. The IGROV-1/OHP and IGROV-1/Pt1 cells, selected for resistance to oxaliplatin and cisplatin respectively, are characterized by a mutant p53 gene. Using the combination index method and cell sensitivity assays, we found a synergistic interaction between ST2782 and bortezomib, more evident in the p53-mutant resistant sublines. Such an interaction was associated with increased apoptotic cell death, as shown by TUNEL assays. The treatment with ST2782 resulted in early induction of the pro-apoptotic protein Bax as well as in cleavage of caspase 3 and PARP only in the resistant cell lines, as supported by Western blot analyses. The inhibition of p53-transcriptional transactivation by pifithrin alpha in IGROV-1 cells enhanced the synergism between the two drugs. Conversely, knockdown of endogenous wild-type p53 in IGROV-1 cells following transfection of small interfering RNAs determined a considerable synergism reduction. These opposite effects support the relevance of the transactivation-deficient mutant p53 as a determinant of the synergism. Moreover, in vivo studies in IGROV-1/Pt1 xenografts indicated that tumor growth inhibition tended to be more marked in mice receiving the drug combination with respect to those treated with bortezomib alone. In conclusion, the present study supports the potential effectiveness of this combination in p53-mutant ovarian cancer models resistant to platinum compounds. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C34.
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