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(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.
Doxsee
Daniel W
DW
Department of Cancer Endocrinology, BC Cancer Agency, Vancouver, British Columbia, Canada.
Gout
Peter W
PW
Kurita
Takeshi
T
Lo
Maisie
M
Buckley
Arthur R
AR
Wang
Yuwei
Y
Xue
Hui
H
Karp
Cristina M
CM
Cutz
Jean-Claude
JC
Cunha
Gerald R
GR
Wang
Yu-Zhuo
YZ
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
D026962:Amino Acid Transport System ASC; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D012460:Sulfasalazine; D003553:Cystine