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(c)(-) 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 xc- transporter and were growth inhibited by SASP (TC50S: 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. (c) 2006Wiley-Liss, Inc.