Verapamil reverts resistance to drug-induced apoptosis in Ki-ras-transformed cells by altering the cell membrane and the mitochondrial transmembrane potentials.

We have previously shown that in vivo ras-transformed cell lines display natural doxorubicin resistance compared with the normal cells and that such resistance is accompanied by a plasma membrane depolarization. In this article we first extend the analysis of doxorubicin effect to other ras-transformed cell lines, which are characterized by an increasing degree of malignant phenotype. Rat thyroid ras-transformed cells are markedly resistant to doxorubicin and the degree of drug resistance correlates with the degree of cell malignancy. The lower amount of drug accumulated inside the malignant and resistant cells is a consequence of their constitutive depolarized membrane potential and may account for their lack of drug-induced apoptosis. Verapamil, a known modulator of drug resistance, is able to decrease the resistance of all the malignant cell lines, initially causing a higher incorporation of doxorubicin as a consequence of its ability to hyperpolarize the membrane potential. In resistant cells, verapamil is also able to alter the mitochondrial membrane potential allowing apoptosis. In conclusion, these studies demonstrate that ras transformation induces the natural resistance to doxorubicin of the malignant cells. We suggest that the most malignant and resistant cells, of metastatic origin, could be preferentially destroyed by manipulation of their membrane properties, and we confirm the possibility of overcoming drug resistance by the administration of verapamil also in P-gp170-nonexpressing cells.