Resistance to verapamil sensitization of multidrug-resistant cells grown as multicellular spheroids

The ability of verapamil to overcome resistance to adriamycin in a multidrug-resistant derivative of the V79 cell line (LZ), grown as multicellular spheroids or as monolayers, was examined. Verapamil was much less effective in overcoming resistance to adriamycin in spheroids than in monolayers. Verapamil increased the adriamycin content of cells grown as monolayers, but had no significant effect on the drug content of spheroids. This occurred in spite of the same mdr-I mRNA and protein levels in monolayers and spheroids. When the surviving fraction of cells was normalized to the cellular adriamycin content, cells both in monolayers and spheroids treated with verapamil were still more sensitive to adriamycin than their counterparts not treated with verapamil. The observed resistance of spheroids to adriamycin and verapamil sensitization may be caused by a drug-resistance mechanism that is functional only in spheroids, in addition to the activity of P-glycoprotein. Multicellular tissue architecture and cell-cell contact may play significant roles in this type of multidrug-resistance mechanism.