Abstract C292: Inhibition of carbonic anhydrase (9 and 12) decreases cell proliferation and gene expression in human glioblastoma cell.

Abstract

Abstract Propose: Glioblastoma (GB) is the most common and lethal malignant primary brain tumor, representing up to 50% of all primary brain gliomas, and carries the poorest prognosis. An important factor for tumor progression is the acidification of the environment that is promoted by carbonic anhydrases (CAs) 9 and 12, directing to the acquisition of metastatic phenotype and chemoresistance to anticancer drugs. Indisulam is a novel anticancer drug with potent inhibition of CAs. It has in vitro and in vivo activity and prevents cell cycle progression in tumor cells, downregulates genes involved in cytotoxic drug resistence and cell proliferation. The aim this study was to evaluate the expression and the effects of inhibition of the 9/12 CAs by indisulam in proliferation and in gene expression of GB cell lines subjected to normoxia or hypoxia. Materials and Method: The U87-MG, U251, U138-MG, U343-MG-a adult GB cell lines were cultured in conditions of hypoxia or normoxia. Functional studies of cell proliferation and clonogenic capacity were performed in triplicate with Indisulan at different concentrations during 24, 48 and 72h. Gene expression of CA9, CA12, VEGF and HIF1α was assessed using qRT-PCR. Statistical analysis was made by one-way ANOVA and Bonferoni post-hoc. Results: Indisulam displayed inhibitory characteristics to hypoxia induced CA9/CA12 expression in the four GBM cell lines. All experiments showed that the inhibition of CA9/12 with indisulam were dose- and time-dependent (p<0.05) and caused a decreased on cell proliferation and the capacity clonogenic. The evaluation of gene expression in conditions of hypoxia (1%) compared to normoxia (preliminary experiments) showed increased expression to the genes CA9, CA12, HIF-1α and VEGF with decreased expression when the cells were treated with Indisulam. Conclusion: Our results indicate antiproliferative and inhibitory effect of the indisulam in GB cell line on condition of normoxic and hypoxic. It suggests that indisulam may be an interesting candidate for the development antitumor therapies based on the inhibition of tumor-associated carbonic anhydrase. Financial Support: FAPESP Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C292. Citation Format: Silvia A. Teixeira, Julia A. Pezuk, Maria S. Brassesco, Carlos G. Carlotti, Luiz G. Tone, Carlos A. Scrideli. Inhibition of carbonic anhydrase (9 and 12) decreases cell proliferation and gene expression in human glioblastoma cell. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C292.