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Reversal of Vinca Alkaloid Resistance but not Multiple Drug Resistance in Human Leukemic Cells by Verapamil¹

Departments of Biochemical and Clinical Pharmacology [W. T. B., M. C. C.] and Hematology-Oncology [A. T.L., R. A. A.], St. Jude Children's Research Hospital, Memphis, Tennessee 38101

We examined the ability of verapamil, a Ca²⁺ channel blocker, to overcome Vinca alkaloid and multiple drug resistance in our CEM/VLB₁₀₀ and CEM/DOX human leukemic lymphoblasts. Compared with the parent CCRF-CEM cells, CEM/VLB₁₀₀ cells are 200- to 800-fold resistant to vinblastine and express cross-resistance to vincristine, doxorubicin, and other "natural product" drugs, as determined by comparing 50% inhibitory concentrations in a 48-h growth inhibition assay. Verapamil (10 µM) decreased the 50% inhibitory concentrations for Vinca alkaloids in CEM/VLB₁₀₀ cells by 75- to 85-fold but caused only slight (2- to 5-fold) decreases in 50% inhibitory concentrations for anthracyclines, epipodophyllotoxins, and other tubulin-binding drugs (colchicine and podophyllotoxin). Qualitatively similar results were obtained with doxorubicin-resistant cells, termed CEM/DOX; verapamil caused a 19-fold increase in doxorubicin toxicity but 67- and 3500-fold increases in the toxicities of vinblastine and vincristine, respectively. These results indicate that the effect of verapamil is relatively greater for Vinca alkaloids, with less pronounced effects for the other natural product drugs against which these cells express multiple drug resistance. In flow cytometric studies, individually nontoxic or minimally toxic concentrations of vinblastine plus verapamil caused measurable accumulation in the G₂ + M phase as early as 4 h after the drug combination was added to cultures of CEM/VLB₁₀₀ cells; this finding correlated with a comparable increase in the number of cells in mitosis and measurable decreases in the total number of cells. Since similar effects on cell cycle distribution, percentage of cells in mitosis, and cell number were seen when CEM/VLB₁₀₀ cells were treated with toxic concentrations of vinblastine alone, we conclude that the primary toxicity of the vinblastine-verapamil combination stems from the alkaloid. Further, the rapid lytic effect of the drug combination was associated with cellular vacuolization. The vacuoles did not stain for lipids, and increases in their number were evident within 2 to 4 h after drug treatment. We suggest that verapamil enhances Vinca alkaloid cytotoxicity by altering "cryptic" cytotoxic targets, possibly related to these vacuoles, through some as yet undefined membrane effect.

¹ Support was provided in part by Research Grant CA-30103 and Cancer Center Support (CORE) Grant CA-21765 from the National Cancer Institute, Bethesda, MD, and by American Lebanese Syrian Associated Charities.

² To whom requests for reprints should be addressed.

Received 6/17/85. Accepted 11/ 5/85.

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