Tumoricidal, Temozolomide- and Radiation-Sensitizing Effects of K(Ca)3.1 K(+) Channel Targeting In Vitro Are Dependent on Glioma Cell Line and Stem Cell Fraction

SIMPLE SUMMARY: A potential new treatment for glioma patients is the blockade of K(Ca)3.1 potassium channels. In our study, we performed experiments with the K(Ca)3.1 blocker TRAM-34 in five glioma cell lines. To broaden our findings, effects on cultures enriched in glioma stem cells which are thought to be responsible for treatment failure and relapse were delineated in addition to standard culture conditions. Accordingly, stem-cell enriched cultures were found to be more resistant towards irradiation therapy. Effects of TRAM-34 were dependent on cell line and culture condition and included direct tumoricidal effects, but also temozolomide- and irradiation-sensitizing effects, showing its synergistic potential with current treatment strategies. TRAM-34 effects were mostly found in stem-cell enriched cultures. Overall, our results underline the importance of testing new interventions in several cell lines and different culture conditions to mimic in vivo inter- and intra-tumoral heterogeneity. ABSTRACT: Reportedly, the intermediate-conductance Ca(2+)-activated potassium channel K(Ca)3.1 contributes to the invasion of glioma cells into healthy brain tissue and resistance to temozolomide and ionizing radiation. Therefore, K(Ca)3.1 has been proposed as a potential target in glioma therapy. The aim of the present study was to assess the variability of the temozolomide- and radiation-sensitizing effects conferred by the K(Ca)3.1 blocking agent TRAM-34 between five different glioma cell lines grown as differentiated bulk tumor cells or under glioma stem cell-enriching conditions. As a result, cultures grown under stem cell-enriching conditions exhibited indeed higher abundances of mRNAs encoding for stem cell markers compared to differentiated bulk tumor cultures. In addition, stem cell enrichment was paralleled by an increased resistance to ionizing radiation in three out of the five glioma cell lines tested. Finally, TRAM-34 led to inconsistent results regarding its tumoricidal but also temozolomide- and radiation-sensitizing effects, which were dependent on both cell line and culture condition. In conclusion, these findings underscore the importance of testing new drug interventions in multiple cell lines and different culture conditions to partially mimic the in vivo inter- and intra-tumor heterogeneity.