Characterization of the catecholamine extraneuronal uptake2 carrier in human glioma cell lines SK-MG-1 and SKI-1 in relation to (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) selective cytotoxicity
Abstract Transport of (2-chloroethyl)-3-sarcosinamide-1-nitrosourea (SarCNU) and (−)-norepinephrine was investigated in SarCNU-sensitive SK-MG-1 and -resistant SKI-1 human glioma cell lines. [ 3 H]SarCNU influx was inhibited by SarCNU, sarcosinamide, and (±)-epinephrine in SK-MG-1 cells with competitive inhibition observed by (±)-epinephrine ( K i = 140 ± 12 μM) and (±)-norepinephrine ( K i = 255 ± 41 μM). No effect on influx was detected in SKI-1 cells. [ 3 H](-)-Norepinephrine influx was linear to 15 sec in both cell lines and temperature dependent only in SK-MG-1 cells. Influx of [ 3 H](−)-norepinephrine was found to be saturable in SK-MG-1 ( K m = 148 ± 28 μM, V max = 1 1.23 ± 0.18 pmol/μL intracellular water/sec) but not in SKI-1 cells. In SK-MG-1 cells, [ 3 H](−)-norepinephrine influx was found to be inhibited competitively by (−)-epinephrine ( K i = 111 ± 7 μM) and SarCNU ( K i = 1.48 ± 0.22 mM). Ouabain and KCl were able to inhibit the [ 3 H](−)-norepinephrine influx in SK-MG-1 cells, consistent with influx being driven by membrane potential. Several catecholamine uptake 2 inhibitors were able to reduce significantly the influx of [ 3 H](−)-norepinephrine and [ 3 H]SarCNU with no inhibition by a catecholamine uptake 1 inhibitor. These findings suggest that increased sensitivity of SK-MG-1 to SarCNU is secondary to enhanced accumulation of SarCNU mediated via the catecholamine extraneuronal uptake 2 transporter, which is not detectable in SKI-1 cells. The introduction of SarCNU into clinical trials will confirm if increased uptake via the catecholamine extraneuronal uptake 2 transporter will result in increased antitumor activity.
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