Nicotine does not affect stem cell properties requisite for suicide gene therapy against glioma

Glioblastoma is one of the most lethal tumors in adult central nervous system with a median survival of a year and half and effective therapeutic strategy is urgently needed. For that reason, stem cell-based suicide gene therapies have attracted much interest because of potent tumor tropism of stem cells and bystander effect. In this current clinical situation, stem cells are promising delivery tool of suicide genes for glioma therapy. Since habitual cigarette smoking still prevails worldwide, we investigated the effect of nicotine on stem cell tropism toward glioma and gap junctional intercellular communication (GJIC) function between glioma and stem cells, both of which are important for suicide gene therapies. Methods: Mouse induced pluripotent stem cell-derived neural stem cells (iPS-NSCs) and human dental pulp mesenchymal stem cells (DPSCs) were used. The effect of nicotine on tumor tropism to glioma-conditioned medium (CM) at a non-cytotoxic concentration was assessed with Matrigel invasion assay. Nicotine effect on GJIC was assessed with the scrape loading/dye transfer (SL/DT) assay for co-culture of glioma and stem cells and the parachute assay among glioma cells using high-content analysis. Results: Tumor tropism of iPS-NSCs toward GL261-CM and DPSCs toward U251-CM was not affected by nicotine (0.1 and 1 µM). Nicotine at the concentrations equivalent to habitual smoking (1 µM) did not affect GJIC of iPS-NSC/GL261 and DPSC/U251 and GJIC among each glioma cells. Conclusions: The study demonstrated that non-cytotoxic concentrations of nicotine did not significantly change the stem cell properties requisite for stem cell-based suicide gene therapy.

Keywords: Nicotine; bystander effect; gap junction; glioma; migration; stem cells.