Enhancement of Melphalan Toxicity by Octanol in Ovarian Adenocarcinoma Cell Lines: Effects of Altered Cell-Cell Communication, Glutathione Levels, and Plasma Membrane Fluidity
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A2780 and COLO-316 ovarian adenocarcinoma cell lines were exposed to 1.0 mM I -octanol for 12 hr in order to evaluate the potential effects of inhibition of gap junction-mediated intercellular communication (GJIC) on cellular responses to the chemotherapeutic drug melphalan. Other cellular endpoints relevant to drug-resistance mechanisms which were monitored after treatments included cellular glutathione levels, glutathione S-transferase activity, mitochondrial membrane potential, and plasma membrane lipid mobility. In cells which were sensitive to melphalan, octanol enhanced melphalan toxicity in the GJIC-competent (A2780/S) but not GJIC-incompetent (COLO-316/S) sensitive cells. Although octanol increases plasma membrane lipid mobility in A2780/S and COLO-316/S, it appears that enhancement of A2780/S sensitivity to melpha Ian may be due to inhibition of GJIC. In melphalan-resistant cells (A2780/R and COLO-316/R), 1.0 mM octanol treatment for 12 hr combined with melphalan reversed the resistance of the cells to the drug. Therefore, alterations in cellular glutathione metabolism and effects on the plasma membrane in addition to uncoupling of GJIC may be involved in sensitizing communication-competent and communication-incompetent resis tant cells because COLO-316/R lacks gap junction-mediated intercellular communication. Further, analysis of mitochon drial membrane potential provided an index of acquired drug resistance and the efficacy of meiphalan and combined octanol/melphalan toxicity. 1995 by the Society of Toxicology.