Effects of glutamate transporter inhibitors on the antitumor activity of doxorubicin.

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.