Non-antitumor vinca alkaloids reverse multidrug resistance in P388 leukemia cells in vitro.

Twelve monomeric or dimeric alkaloids from Vinca rosea Linn., which had been reported to have little or no antitumor activity, were investigated to determine their combined effects with either vincristine or daunorubicin on in vitro cell growth of a P388 subline resistant to vincristine and cross-resistant to anthracyclines. We found that the combinations at subcytotoxic concentrations induced significant growth inhibition of the resistant cells, but not of the sensitive cells. Of the alkaloids examined, catharine, vindoline, catharanthine, vincarodine, and lochnerine were able to bring about complete inhibition of cell growth. Further in vitro study using vindoline revealed that at 10 micrograms/ml it was able to completely reverse not only resistance to vincristine but also cross-resistance to vinblastine, daunorubicin, and adriamycin. In addition, we found that vinca alkaloids active in reversing resistance possess potent activities to enhance the net uptake of not only vincristine but also daunorubicin by the resistant cells, and this effect was proved to result from their inhibitory action on the active efflux process. These results provide further support for our hypothesis that both anthracyclines and vinca alkaloids can inhibit their own efflux process by interacting with the cell membrane, and this similarity provides a basis for their reciprocal cross-resistance, irrespective of their different chemical structures.