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Biochemical and cytological effects of the anticancer alkaloid, acronycine, on tumor cells in culture Dunn, Bruce Partridge

Abstract

Acronycine is an acridone alkaloid occurring in the bark of the Australian scrub ash. It has been reported to have considerable anti-tumor activity against a variety of experimental neoplasms, and is currently undergoing clinical trials. Little is known of the mechanisms responsible for its antitumor activity. The current study describes some of the cytological and biochemical effects of the alkaloid on tumor cells in culture. The growth in vitro of L5I78Y mouse and IRC rat leukemia cells was inhibited by acronycine at concentrations of 3 to 12 μ the incorporation of extracellular nucleosides into intracellular nucleic acid precursor pools - this effect appeared to account entirely for the inhibition of the incorporation of these precursors into nucleic acids. The mechanism by which L5I78Y cells utilize extracellular uridine and by which acronycine interferes with this process were studied. The results of investigations into the kinetics and temperature dependence of uridine uptake by whole cells and of uridine phosphorylation by cell extracts suggested that: (i) the transport of uridine across the plasma membrane is a step independent from its subsequent phosphorylation, and (ii) this transport is normally rate-limiting in the uptake of this nucleoside. Acronycine, at concentrations which markedly inhibited uridine uptake in whole cells, had little or no effect on the phosphorylation of uridine in cell extracts. This and other evidence (including the effect of acronycine on the temperature dependence and kinetics of uridine uptake) suggested that the inhibition by acronycine of the utilization by L5I78Y cells of extracellular uridine results from an interference with the transport of the nucleoside across the plasma membrane. A similar mechanism may also account for the inhibition of the uptake of other nucleosides, as well as for a slight inhibition of choline and inositol uptake which was also observed in this study. 14C-acronycine was prepared and shown to be bound rapidly and reversibly to L5I78Y cells. It was also bound to non-dialysable serum components, in which form it appeared to no longer be available for interaction with cells. This latter effect may have implications for the us of acronycine in chemotherapy. Most or all of the observed effects of acronycine can tentatively be explained on the basis of a akaloid-induced alterations in membrane function. Acronycine is a relatively water-insoluble, lipophilic compound, and as such may reasonably be expected to interact with lipids and/or hydrophobic regions of proteins. It is speculated that interactions of this type with membrane components may be responsible for the biological effects of this compound.

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