Abstract B18: Targeting histone deacetylase 6 (HDAC6) depresses proliferation and induces caspase-associated cell death in glioblastoma multiforme (GBM) cells and GBM stem cell-like spheroids

Abstract

Abstract Glioblastoma multiforme (GBM) comprises the most common and very aggressive form of primary brain tumor with a dismal prognosis and very poor response to the current therapies. HDAC inhibitors (HDACi) are capable of inducing growth arrest and apoptosis in various tumor cell types. HDAC6 is a unique enzyme having two deacetylase domains, and a ubiquitin-binding domain. HDAC6 interacts with a number of proteins in the cytoplasm and is involved in tumorigenesis, cell motility, and metastasis. Significantly, it has been shown that HDAC6 knockout mice are viable. Therefore, in this study, we evaluated HDAC6 as a relevant target for GBM treatment by using a potent HDAC6 inhibitor, CAY 10603. Our data showed that CAY 10603 targets the established GBM cell line U86MG, M-HBT161 early primary cultures, and CD133- and SOX2-positive stem cell-like spheroids. CAY 10603 at 1-5 μM triggered significant inhibition of cell survival and induced apoptotic cell death in GBM cells and GBM spheroids. CAY 10603 reduced cell survival in these cells by 50% (IC50) at 1-3 μM treatment for 48 h. Similarly, CAY 10603 induced significant dose-dependent inhibition of spheroid survival in U87MG and M-HBT161 when the spheroids were grown in a defined GBM stem cell (GSC) growth medium on ultra-low attachment plates for four days. Interestingly, when grown in the same medium but on plates which promote attachment, the spheroids were 3-4 fold more sensitive to CAY 10603, indicating that growth conditions affect the sensitivity of GBM stem cell-like spheroids. Moreover, CAY 10603 triggered cell death in U87MG and M-HBT161 cells as well as CD133/SOX2-expressing spheroids was associated with activation of caspases-3, -6 and -9. Overall, our results show that CAY 10603 robustly inhibits the growth of GBM cells, and is effective in eliminating spheroids that contain GBM cancer stem cells which play a major role in drug resistance and disease recurrence. These results suggest that use of CAY 10603 alone or in combination with other agents may potentially improve the survival of brain tumor patients. Citation Format: Mohammad Reza Saadatzadeh, Khadijeh Bijangi Vishehsaraei, Haiyan Wang, Aaron Cohen-Gadol, Karen E. Pollok, Ahmad R. Safa. Targeting histone deacetylase 6 (HDAC6) depresses proliferation and induces caspase-associated cell death in glioblastoma multiforme (GBM) cells and GBM stem cell-like spheroids. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B18.