Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

Multidrug resistance can be reversed by a range of "calcium channel"-blocking drugs in vitro, of which verapamil is the most widely used. Verapamil is bound to alpha 1-acid glycoprotein (AAG) in vivo in humans but is absent from calf serum, used in tissue culture media. The effect of AAG on the ability of verapamil to alter Adriamycin cytotoxicity was assessed in parental Chinese hamster ovary cells (CHO-K1) and in a multidrug-resistant subline (CHO-Adrr). In both the parental and the resistant cells, there was a dose-related potentiation of Adriamycin cytotoxicity by verapamil. At 10 microM verapamil, there was a 5-fold decrease in the concentration of Adriamycin that caused 50% reduction in growth of CHO-K1 cells but a 15-fold decrease in CHO-Adrr cells. In the presence of increasing AAG concentrations within the range found in cancer patients, there was a concentration-related reduction in the effects of verapamil. In CHO-Adrr cells, there was complete reversal of the potentiating effect of 10 microM verapamil at 2 mg/ml AAG. In contrast, in CHO-K1 cells, AAG reduced the effects of verapamil by only 20% at a similar concentration. There was a much higher internal uptake of fluorescein-labeled AAG by CHO-Adrr cells than by CHO-K1 cells. These results suggest that, in addition to a plasma membrane site, there may be a major endosomal site of action of verapamil in multidrug-resistant cells. The implications are that verapamil in vivo in the presence of AAG may effectively reverse low levels of multidrug resistance, but not high levels. Thus selection of patients with low AAG levels may be appropriate for clinical studies.


Journal article


Cancer Res

Publication Date





2818 - 2822


ATP Binding Cassette Transporter, Subfamily B, Member 1, Animals, Cell Line, Cricetinae, Doxorubicin, Drug Resistance, Drug Synergism, Membrane Glycoproteins, Orosomucoid, Verapamil