Cystine-glutamate transporter SLC7A11 mediates resistance to geldanamycin but not to 17-(allylamino)-17-demethoxygeldanamycin.
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, "17-O/H" (C-17 methoxy or unsubstituted) and "17-N" (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.
Liu
Ruqing
R
Division of Pharmacogenomics and Molecular Epidemiology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, USA.
Blower
Paul E
PE
Pham
Anh-Nhan
AN
Fang
Jialong
J
Dai
Zunyan
Z
Wise
Carolyn
C
Green
Bridgette
B
Teitel
Candee H
CH
Ning
Baitang
B
Ling
Wenhua
W
Lyn-Cook
Beverly D
BD
Kadlubar
Fred F
FF
Sadée
Wolfgang
W
Huang
Ying
Y
D027182:Amino Acid Transport System y+ / Q000378:metabolism*; D016227:Benzoquinones / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000502:physiology*; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D027182:Amino Acid Transport System y+; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; C118895:SLC7A11 protein, human; C112765:tanespimycin; C001277:geldanamycin