For biochemical modulation, components of
green tea have been shown to be useful modulators in combination with
doxorubicin (DOX). We have confirmed that
theanine enhances the antitumor activity of DOX due to inhibition of DOX efflux from
tumor cells. Because
theanine is a
glutamate analogue, we found that it is associated with a change in the
drug transport system on the
tumor cell membrane, in particular
glutamate transporters. We examined the effect of
dihydrokainate (DHK), one of the useful
glutamate transporter inhibitors. DHK also inhibits DOX efflux significantly and reduces the
glutamate uptake by Ehrlich
ascites carcinoma cells. The potential contribution of
glutamate transporters not only to
glutamate uptake but also to cell membrane export of DOX has been shown. In addition, the combination of DHK with DOX significantly enhances the antitumor activity of DOX, by 1.8-fold (P<0.001). The DOX concentration in
tumors significantly increases on combination with DHK and is correlated with the reduced
tumor weight. On the other hand, DHK tends to reduce the DOX concentration in normal tissues. We expect that DHK has different actions in
tumor and normal tissues because different
isoforms of
glutamate transporters are expressed in the two tissues. Thus, the results suggest that DHK is a novel and useful modulator for inducing enhancement of antitumor activity.