Differential effects of verapamil and quinine on the reversal of doxorubicin resistance in a human leukemia cell line

Sanae Bennis, François Ichas, Jacques Robert
Int. J. Cancer. 1995-07-28; 62(3): 283-290
DOI: 10.1002/ijc.2910620309

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We studied the restoration of doxorubicin accumulation and sensitivity by
verapamil and quinine in a variant of the human erythroleukemia cell line K562
selected for resistance to doxorubicin and presenting a multidrug-resistance
(MDR) phenotype. Verapamil was able to completely restore doxorubicin
accumulation in the resistant cells to the level obtained in sensitive cells, but
only partially reversed doxorubicin resistance. Quinine, in contrast, had a
relatively weak effect on doxorubicin accumulation but was able to completely
restore doxorubicin sensitivity in the resistant cells. In addition, verapamil
was able to decrease azidopine binding to P-glycoprotein, whereas quinine was
not. Quinine also modified the intracellular tolerance to doxorubicin, which
suggests that it is able to modify drug distribution within the cells. Confocal
microscopy revealed that verapamil and quinine were able to restore nuclear
fluorescence staining of doxorubicin in resistant cells; since this was obtained
for quinine without significant increase of doxorubicin accumulation, this
observation confirms that quinine acts principally on doxorubicin redistribution
within the cells, allowing the drug to reach its nuclear targets. When used in
association, verapamil and quinine reversed doxorubicin resistance in a
synergistic fashion. We conclude that verapamil and quinine do not share the same
targets for reversal of MDR in this cell line; whereas verapamil directly
interferes with P-glycoprotein and mainly governs drug accumulation, quinine has
essentially intracellular targets involved in drug redistribution from
sequestration compartments.


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