The Prostate 67:162^171 (2007) Sulfasalazine-Induced Cystine Starvation: Potential Use for Prostate CancerTherapy Daniel W. Doxsee, 1 Peter W. Gout, 1 * Takeshi Kurita, 1 Maisie Lo, 2 Arthur R. Buckley, 3 Yuwei Wang, 1 Hui Xue, 1 Cristina M. Karp, 4 Jean-Claude Cutz, 5 Gerald R. Cunha, 6 and Yu-Zhuo Wang 1 1 Department of Cancer Endocrinology, BCCancer Agency,Vancouver, British Columbia,Canada 2 Department of Cancer Genetics, BCCancer Agency,Vancouver, British Columbia,Canada 3 College of Pharmacy,University of Cincinnati Medical Center,Cincinnati,Ohio 4 Center for Advanced Biotechnology and Medicine, Rutgers University, Picataway, New Jersey 5 Department of Applied Molecular Oncology,Ontario Cancer Institute University Health Network, Toronto,Ontario,Canada 6 Department of Anatomy,UCSF School of Medicine,University of California, San Francisco,California 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 c  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 prolifera- tion; both cell lines expressed the x c  transporter and were growth inhibited by SASP (IC 50 s: 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 67: 162–171, 2007. # 2006 Wiley-Liss, Inc. KEY WORDS: x c  ; cystine/glutamate antiporter; cystine starvation; glutathione; sub- renal capsule xenograft INTRODUCTION Prostate cancer is the most common cancer as well as the second leading cause of cancer-related deaths for North American males. Most deaths from this disease are due to metastases that are resistant to conventional therapies. Although androgen ablation, currently the treatment of choice, can initially lead to substantial remissions, tumors frequently return in an androgen- independent form that is highly resistant to further hormonal therapy and other available regimens, Grant sponsor: Canadian Institutes of Health Research (to P.W.G./ Y.Z.W.); Grant sponsor: BC Cancer Foundation (to P.W.G.); Grant sponsor: National Cancer Institute of Canada (to Y.Z.W.); Grant sponsor: US Army Department of Defense (to Y.Z.W./P.W.G.); Grant number: USAMRMC W81XWH-04-1-0290. *Correspondence to: Peter W. Gout, PhD, Department of Cancer Endocrinology, BC Cancer Agency—Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada V5Z 1L3. E-mail: pgout@bccrc.ca Received 28 March 2006; Accepted 22 May 2006 DOI 10.1002/pros.20508 Published online 30 October 2006 in Wiley InterScience (www.interscience.wiley.com). ß 2006 Wiley-Liss, Inc.