@article {Liu1637, author = {Ruqing Liu and Paul E. Blower and Anh-Nhan Pham and Jialong Fang and Zunyan Dai and Carolyn Wise and Bridgette Green and Candee H. Teitel and Baitang Ning and Wenhua Ling and Beverly D. Lyn-Cook and Fred F. Kadlubar and Wolfgang Sad{\'e}e and Ying Huang}, title = {Cystine-Glutamate Transporter SLC7A11 Mediates Resistance to Geldanamycin but Not to 17-(Allylamino)-17-demethoxygeldanamycin}, volume = {72}, number = {6}, pages = {1637--1646}, year = {2007}, doi = {10.1124/mol.107.039644}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {The cystine-glutamate transporter SLC7A11 has been implicated in chemoresistance, by supplying cystine to the cell for glutathione maintenance. In the NCI-60 cell panel, SLC7A11 expression shows negative correlation with growth inhibitory potency of geldanamycin but not with its analog 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), which differs in the C-17 substituent in that the the methoxy moiety of geldanamycin is replaced by an amino group. Structure and potency analysis classified 18 geldanamycin analogs into two subgroups, {\textquotedblleft}17-O/H{\textquotedblright} (C-17 methoxy or unsubstituted) and {\textquotedblleft}17-N{\textquotedblright} (C-17 amino), showing distinct SLC7A11 correlation. We used three 17-O/H analogs and four 17-N analogs to test the role of the 17-substituents in susceptibility to SLC7A11-mediated resistance. In A549 cells, which are resistant to geldanamycin and strongly express SLC7A11, inhibition of SLC7A11 by (S)-4-carboxyphenylglycine or small interfering RNA increased sensitivity to 17-O/H, but had no effect on 17-N analogs. Ectopic expression of SLC7A11 in HepG2 cells, which are sensitive to geldanamycin and express low SLC7A11, confers resistance to geldanamycin, but not to 17-AAG. Antioxidant N-acetylcysteine, a precursor for glutathione synthesis, completely suppressed cytotoxic effects of 17-O/H but had no effect on 17-N analogs, whereas the prooxidant ascorbic acid had the opposite effect. Compared with 17-AAG, geldanamycin led to significantly more intracellular reactive oxygen species (ROS) production, which was quenched by addition of N-acetylcysteine. We conclude that SLC7A11 confers resistance selectively to 17-O/H (e.g., geldanamycin) but not to 17-N (e.g., 17-AAG) analogs partly as a result of differential dependence on ROS for cytotoxicity. Distinct mechanisms could significantly affect antitumor response and organ toxicity of these compounds in vivo. The American Society for Pharmacology and Experimental Therapeutics}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/72/6/1637}, eprint = {https://molpharm.aspetjournals.org/content/72/6/1637.full.pdf}, journal = {Molecular Pharmacology} }