Sulfasalazine-induced cystine starvation: Potential use for prostate cancer therapy

BACKGROUND Certain cancers depend for growth on uptake of cystine/cysteine from their environment. Here we examined advanced human prostate cancer cell lines, DU-145 and PC-3, for dependence on extracellular cystine and sensitivity to sulfasalazine (SASP), a potent inhibitor of the x cystine transporter. METHODS Cultures were evaluated for growth dependence on exogenous cystine, x transporter expression, response to SASP (growth and glutathione content). In vivo, effect of SASP was determined on subrenal capsule xenograft growth. RESULTS Cystine omission from culture medium arrested DU-145 and PC-3 cell proliferation; both cell lines expressed the x transporter and were growth inhibited by SASP (IC50s: 0.20 and 0.28 mM, respectively). SASP-induced growth inhibition was associated with vast reductions in cellular glutathione content—both effects based on cystine starvation. SASP (i.p.) markedly inhibited growth of DU-145 and PC-3 xenografts without major toxicity to hosts. CONCLUSIONS SASP-induced cystine/cysteine starvation leading to glutathione depletion may be useful for therapy of prostate cancers dependent on extracellular cystine. Prostate © 2006 Wiley-Liss, Inc.