Malignant glioma, characterized by widespread invasion throughout the normal brain and resistance to chemotherapy, represents one of the most difficult types of cancer to treat. Since multiple biochemical and genetic alterations are associated with glioma, a single agent to hit one molecular target may not be sufficient to treat this disease. Targeting molecular chaperone Hsp90 may offer many advantages for glioma therapy due to its simultaneous regulation of various oncogenic proteins. However, one of the major obstacles of successful glioma therapy is the development of resistance to various types of Hsp90 inhibitors, such as celastrol and geldanamycin and its derivative 17-AAG. The purpose of this study is to identify novel determinants for sensitivity and resistance to this group of drugs. To facilitate a systematic study of chemosensitivity across a group of Hsp90 inhibitors, we correlated mRNA expression profiles of majority of membrane transporters presently known to be relevant to drug response with anticancer activities of representative Hsp90 inhibitors in 60 tumor cell lines (NCI-60). Using this pharmacogenomic approach, we found that the expression of SLC7A11 (or xCT), the gene encoding the light subunit of the xc- amino acid transporter, negatively correlated with several Hsp90 inhibitors such as geldanamycin and celastrol, but not with the geldanamycin derivative 17-AAG. We subsequently validated the gene-drug correlations obtained from the pharmacogenomic prediction using cytotoxicity assay on glioma cell lines in the presence or absence of sulfasalazine, an established anti-inflammatory drug which at low levels specifically inhibits cellular cystine uptake mediated by the xc- plasma membrane cystine transporter. We found that use of sulfasalazine at patient-tolerated levels (0.15 mM) significantly enhanced growth-inhibitory activity of geldanamycin and celastrol. In conclusion, our study demonstrated the importance of the xc- cystine transporter SLC7A11 as a target for sensitizing glioma to Hsp90 inhibitors. Treatment with sulfasalazine led to sensitization of the glioma cells to Hsp90 inhibitors via inhibiting the xc- transporter. This study also indicates that sulfasalazine, a relatively inexpensive and non-toxic FDA-approved drug may, by inhibiting cystine transporter and subsequently inducing glutathione depletion, be useful for combination therapy of gliomas.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 915.

100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO