Sulfa salazine-Induced Cystine Starvation: Potential Use for Prostate Cancer Therapy

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Abstract

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 xc- cystine transporter.

METHODS.

Cultures were evaluated for growth dependence on exogenous cystine, xc- 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 (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.

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