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(The FASEB Journal. 2001;15:2702-2714.)
© 2001 FASEB

Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase {pi}

SHINJI GOTO*, YOSHITO IHARA*, YOSHISHIGE URATA*, SHINICHI IZUMI{dagger}, KUNIKO ABE{dagger}, TAKEHIKO KOJI{dagger} and TAKAHITO KONDO*

* Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, and
{dagger} Department of Histology and Cell Biology, Nagasaki University School of Medicine, Nagasaki 852-8523, Japan

1Correspondence: Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University School of Medicine, Nagasaki, 852-8523, Japan. E-mail: kondo{at}net.nagasaki-u.ac.jp

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. —Goto, S., Ihara, Y., Urata, Y., Izumi, S., Abe, K., Koji, T., Kondo, T. Doxorubicin-induced DNA intercalation and scavenging by nuclear glutathione S-transferase {pi}.


Key Words: Glutathione S-transferase {pi} • doxorubicin • cisplatin • nuclear transfer • DNA damage




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