Drug Repositioning Screen on a New Primary Cell Line Identifies Potent Therapeutics for Glioblastoma

Abstract

Glioblastoma is a malignant brain cancer with limited treatment options and high mortality rate. While established glioblastoma cell line models provide valuable information, they ultimately lose most primary characteristics of tumors under long-term serum culture conditions. Therefore, established cell lines do not necessarily recapitulate genetic and morphological characteristics of real tumors. In this study, in line with the growing interest in using primary cell line models derived from patient tissue, we generated a primary glioblastoma cell line, KUGBM8 and characterized its genetic alterations, long term growth ability, tumor formation capacity and its response to Temozolomide, the front-line chemotherapy utilized clinically. In addition, we performed a drug repurposing screen on the KUGBM8 cell line to identify FDA-approved agents that can be incorporated into glioblastoma treatment regimen and identified Topotecan as a lead drug among 1,200 drugs. We showed Topotecan can induce cell death in KUGBM8 and other primary cell lines and cooperate with Temozolomide in low dosage combinations. Together, our study provides a new primary cell line model that can be suitable for both in vitro and in vivo studies and suggests that Topotecan can offer promise as a therapeutic approach for glioblastoma.

Chronically radiation-exposed survivor glioblastoma cells display poor response to Chk1 inhibition

“…Except for KUGBM8 cells, all the cells used in the study were p53 mutant. Like most glioblastoma tumors and established cell lines, radiation response depends not solely on one gene or a pathway but on various components of tumor progression [49], [51].…”

“…This way, we succeeded in generating age-matched parental/radiation-survivor (IR-Surv) cell line pairs. To examine the survival capacities of glioblastoma cell lines with different genetic landscapes, we utilized 1 primary cell line generated in our laboratory, and 3 established cell lines [49]. However, the endurance levels of cell lines to total IR treatment were variable.…”

“…Cell Culture and Reagents: Glioblastoma cell lines U373, LN229, and T98G were available from the American Tissue Type Culture Collection (USA). KUGBM8 primary cell line was established by Dr. Filiz Şenbabaoğlu from patient samples in collaboration with Koç University Hospital Neurosurgery Department [49]. Protocol of primary cell line generation was adapted from [69].…”

Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia

“…This way, we succeeded in generating age-matched parental/irradiation-survivor (IR-Surv) cell line pairs. To examine the survival capacities of glioblastoma cell lines with different genetic landscapes, we utilized one primary cell line generated in our laboratory and three established cell lines [48]. However, the endurance levels of cell lines to total IR treatment were variable.…”

“…Except for KUGBM8 cells, all the cells used in the study were p53 mutant. Like most glioblastoma tumors and established cell lines, radiation response depends not solely on one gene or a pathway but on various components of tumor progression [48,50].…”