RT Journal Article
SR Electronic
T1 Role of membrane potential in the accumulation of quaternized ellipticines by human tumor cell lines.
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 1018
OP 1025
VO 279
IS 2
A1 Vistica, D T
A1 Kenney, S
A1 Hursey, M
A1 Boyd, M R
YR 1996
UL http://jpet.aspetjournals.org/content/279/2/1018.abstract
AB 9-Methoxy-N2-methylellipticinium acetate (MMEA) is representative of a series of quaternized ellipticines that exhibited selective cytotoxicity for human brain tumor cell lines of glial origin in the in vitro primary screen of the U.S. National Cancer Institute. The present investigation was initiated to determine whether membrane potential contributes to the cellular accumulation of this lipophilic cation by selected brain tumor and non-brain tumor cell lines. The results indicate that accumulation of MMEA by drug-sensitive cell lines, but not drug-resistant cell lines, is reduced by experimental conditions that depolarize the plasma membrane, e.g., stepped increases in the extracellular potassium concentration. These experimental conditions result in increased cellular fluorescence of cells stained with the voltage-sensitive anionic dye bis(1,3-dibutylbarbituric acid)trimethine oxonol, suggesting that decreased accumulation of MMEA is the result of decreased membrane potential. Membrane potential measurements using the null point method indicated that the mean membrane potential of selected MMEA-sensitive cell lines (-39.4 +/- 6.8 mV) was significantly lower (P < .005) than MMEA-resistant cell lines (-17 +/- 3.8 mV). Ultrastructural studies with the MMEA-sensitive U-251 glioblastoma indicated that the first morphological effects of MMEA occurred in mitochondria, where dissolution of cristae was observed, followed by engulfment of mitochondria in multilamellar phagocytic vesicles. Electron microscopic autoradiographic studies with tritium-labeled MMEA revealed that the drug was localized in mitochondria and nuclei.