The Effect of Hydroquinidine on Proliferation and Apoptosis of TMZ-sensitive and -resistant GBM Cells.

Abstract

Glioblastoma multiforme (GBM) is a lethal form of central nervous system cancer with a lack of efficient therapy options. Aggressiveness and invasiveness of the GBM result in poor prognosis and low overall survival. Therefore, the necessity to develop new anti-carcinogenic agents in GBM treatment is still a priority for researchers. Ion channels are one of the primary regulators of physiological homeostasis with additional critical roles in many essential biological processes related to cancer, such as invasion and metastasis. A multi-channel blocker, hydroquinidine (HQ), is currently in use to treat short-QT and Brugada arrhythmia syndromes. The objective of the study was to examine the alterations in survival, clonogenicity, migration, tumorigenicity, proliferation, apoptosis, and gene expression profile of temozolomide (TMZ)-sensitive and TMZ-resistant GBM cells upon HQ treatment. The possible anti-neoplastic activity of HQ on GBM cells was investigated by several widely applied cell culture methods. The IC50 values were determined using the MTT assay. Upon HQ treatment, the clonogenicity and migration capacity of cells were evaluated via colony-formation and wound healing assay, respectively. For antiproliferative and apoptotic effects, EdU and CFSE, and Annexin-V labeling were applied. Tumorigenicity level was depicted by employing soft agar assay. The expression level of multiple genes functioning in the cell cycle and apoptosis- related processes was checked utilizing qPCR. A significant anti-carcinogenic effect of HQ on TMZ-sensitive and -resistant GBM cells characterized by the increased apoptosis and decreased proliferation rate was revealed due to the altered gene expression profile related to cell cycle and cell death. In this study, the anti-carcinogenic effect of HQ has been demonstrated for the first time. Our data suggest the possible utilization of HQ to suppress the growth of GBM cells. Further studies on GBM-bearing animal models are required to assess its therapeutic potential in GBM treatment.