Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase π

Glutathione S-transferase (GST) functions in xenobiotic biotransformation and drug metabolism. Increased expression of GST pi, an isozyme of GST, has been found in cancer cells resistant to doxorubicin hydrochloride (DOX) or cis-diamminedichloroplatinum (II) (CDDP), and this increase was believed to be correlated with drug resistance of cancer cells. GST is mainly expressed in the cytoplasm; GST pi in the nucleus has been reported in cancer cells, but the meaning of this result is not known. Here, we studied changes in the amount of nuclear GST pi after exposure of cancer cells to anticancer drugs, and role of the nuclear GST pi in drug resistance. We found nuclear GST pi in cancer cells resistant to DOX, and the amount of nuclear GST pi was enhanced by treatment of the cancer cells with DOX or CDDP. We also found that a mushroom lectin, an inhibitor of nuclear transport, inhibited the nuclear transfer of GST pi, suggesting the existence of a specific transport system for the nuclear transfer of GST pi. Nuclear GST pi protected DNA against damage by anticancer drugs. These results suggest a possible role of GST pi in the acquisition of resistance to anticancer drugs by cancer cells.