Abstract B53: Sonic Hedgehog inhibition in glioblastoma potentializes temozolomide effect?

Abstract

Abstract Gliomas are malignant intracranial tumors and may occur in any region of central nervous system (CNS). Among them, glioblastoma (GBM) is the most aggressive and frequent brain tumors. In GBM treatment, the alkylating agent temozolomide (TMZ) is the first-line chemotherapy used; however, the patients' prognosis remains limited. During tumorigenesis, several signaling pathways vital for embryonic development are activated or inhibited, such as transforming growth factor beta (TGFbeta), Wingless (Wnt), and Sonic hedgehog (Shh). Currently, it is known that Shh pathway is involved in the chemoresistance of GBMs, and most of them have this pathway constitutive activated, which is one of the factors responsible to resistance to TMZ treatment. The limitation of using TMZ treatment can be solved by the identification of cell type with stem cell-like properties, the cancer stem cells (CSCs). To overcome this problem, some selective inhibitory drugs of Shh pathway have been developed, such as GANT-61. In this work, we investigated if Shh inhibition potentiates the effects of TMZ and verified the mechanisms involved in this process. To achieve our goals, GBM11 and T98G cell lines were treated with TMZ (100, 200, and 400 μM) and GANT-61 (20 μM) at different times of incubation. Our results suggest that both cell lines are resistant to TMZ, and the combination of GANT-61 with TMZ during 72 h reduced the cell viability of T98G lineage by MTT assay. Also, our results suggest that among the mechanisms involved in the cell viability reduction observed by combination of TMZ+GANT, cell death occurs due to DNA fragmentation and loss of membrane integrity, as well as formation of acidic vesicles that are indicative of autophagy and reactive oxygen species (ROS) production. In short, our results suggest that selective inhibition of the Shh pathway by GANT-61 is potentiating the effect of TMZ, being a promising strategy for GBMs treatment. Citation Format: Jessica Honorato, Giselle Pinto de Faria Lopes, Gabriela Basile, Vivaldo Moura-Neto, Tania Spohr. Sonic Hedgehog inhibition in glioblastoma potentializes temozolomide effect? [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B53.