title: Sulfasalazine-induced cystine starvation: potential use for prostate cancer therapy.
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 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 proliferation; 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.
authors.affiliation: Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Doxsee
authors.forename: Peter W
authors.initials: PW
authors.lastname: Gout
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kurita
authors.forename: Maisie
authors.initials: M
authors.lastname: Lo
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Buckley
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Xue
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Karp
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Cutz
authors.forename: Gerald R
authors.initials: GR
authors.lastname: Cunha
authors.forename: Yu-Zhuo
authors.initials: YZ
authors.lastname: Wang
mesh_terms: D026962:Amino Acid Transport System ASC / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003553:Cystine / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012460:Sulfasalazine / Q000378:metabolism / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D026962:Amino Acid Transport System ASC; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D012460:Sulfasalazine; D003553:Cystine