Dihydrokainate, a
glutamate transporter inhibitor, was previously found to be a useful modulator of antitumor activity of
doxorubicin (DOX).
Dihydrokainate prevented an efflux of DOX by inhibiting the uptake of
glutamate by
tumor cells. We examined the potential of
glutamate transporter inhibitors as modulators of DOX activity. We observed a significant reduction in the uptake of
glutamate by other inhibitors and a similar effect on DOX efflux in M5076 ovarian
sarcoma cells. However, in vivo, the tissue distribution of each
isoform is different, and
glutamate transporter inhibitors with different affinities for each
isoform affected
tumors and normal tissues differently.
L-Serine-O-sulfate, which has high affinity to
glutamate/aspartate transporter, particularly enhanced the antitumor activity of DOX in M5076
tumor-bearing mice. In contrast, L-alpha-aminoadipate tended to increase the DOX concentration in normal tissues rather than
tumors. It was shown that the relation between
glutamate transporter isoforms and the selective affinity of inhibitors could selectively affect the antitumor activity and side effects of DOX. Furthermore, the effects of inhibitors varied among cells expressing different
isoforms. Notably, a low concentration of
L-serine-O-sulfate actually increased the uptake of
glutamate in
P388 leukemia cells.