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Anthracycline-induced Inhibition of a Calcium Action Potential in Differentiated Murine Neuroblastoma Cells

Department of Oncology [K. S. S., G. P.] and Department of Pharmacology, [S. G. O., S. R. T.] Mayo Clinic and Foundation, Rochester, Minnesota 55904

The effects of some anthracyclines on a Ca²⁺-dependent action potential have been studied in differentiated murine neuroblastoma cells (N1E-115 clone). The differentiated neuroblastoma cell possesses characteristics of an electrically excitable cell and can generate propagated potential spikes in which Ca²⁺ is the inward charge carrier. This was shown by the fact that action potentials recorded from differentiated neuroblastoma cells in the presence of 10^-7 g of tetrodotoxin per ml, which inhibits active Na⁺ channels, had a spike amplitude that depended upon the extracellular Ca²⁺ concentration in a manner close to that predicted by the Nernst equation. The peak potential changed 28.9 mV/decade change in extracellular Ca²⁺. Local application to a cell of 10^-8 M doxorubicin produced inhibition of this Ca²⁺-dependent action potential within 5 s of drug application and a maximum inhibition of 13% 60 s after drug application. There was almost complete recovery to the initial spike amplitude value within 10 min after removing drug. The same concentration of doxorubicin also produced complete inhibition, without recovery, of a Ca²⁺-dependent after-discharge which followed the initial action potential in about half the cells studied. Increasing concentrations of doxorubicin produced dose-dependent inhibition of the initial Ca²⁺-dependent action potential. Cells exposed to 10^-5 M doxorubicin showed 88% inhibition of the Ca²⁺-dependent action potential with no recovery even 10 min after removing the drug. Daunomycin, 10^-6 M, produced 90% inhibition of the Ca²⁺-dependent action potential. Daunomycin aglycone (10^-6 M), which lacks antitumor activity, had no significant effect on the Ca²⁺-dependent action potential. The rapid onset of the drug-induced response together with the low concentrations of anthracyclines needed to inhibit voltage-dependent Ca²⁺ channels in the neuroblastoma cells suggest a direct effect of anthracyclines on the cell surface membrane. The findings are discussed in light of the possible role of Ca²⁺ in cancer cells.

¹ Recipient of support from NIH Cancer Research Training Grant CA 09441.

² Recipient of support from NIH Pharmacology Research Training Grant GM 07624.

³ To whom requests for reprints should be addressed, at Department of Oncology, Mayo Clinic and Foundation, 200 First Street, S. W., Rochester, MN 55905.

Received 7/22/85. Revised 11/27/85. Revised 2/18/86. Accepted 2/21/86.