The xc- cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine.
OBJECTIVE
To determine whether the xc- cystine transporter could be a useful therapeutic target for small-cell lung cancer (SCLC).


METHODS
Human SCLC cell cultures were examined for growth dependence on extracellular cystine, xc- expression, glutathione levels and response to highly specific xc- inhibitors, i.e., monosodium glutamate (MSG) and the anti-inflammatory drug, sulfasalazine (SASP). In studying tumor growth inhibition by SASP, use was also made of a novel SCLC tissue xenograft model, LU6-SCLC, derived from a chemoresistant patient's SCLC specimen.


RESULTS
Growth of NCI-H69 and NCI-H82 SCLC cells greatly depended on xc- -mediated uptake of cystine. SASP substantially reduced their glutathione levels (>70%; 0.3 mM SASP; 24 h) and growth (72 h) with IC(50)s of 0.21 and 0.13 mM, respectively; MSG also inhibited growth markedly. Both SASP- and MSG-induced growth arrests were largely prevented by cystine uptake-enhancing 2-mercaptoethanol (66 approximately microM) indicating they were primarily due to cystine starvation. Without major side-effects, SASP (i.p.) restrained growth of NCI-H69 cell xenografts (approximately 50%) and, importantly, substantially inhibited growth of the clinically more relevant LU6-SCLC tissue xenografts (approximately 70% by stereological analysis), reducing tumor glutathione contents.


CONCLUSIONS
The xc- cystine/glutamate antiporter is potentially useful as a target for therapy of SCLC based on glutathione depletion. Sulfasalazine may be readily used for this approach, especially in combination chemotherapy.
Guan
Jun
J
Department of Cancer Endocrinology, BC Cancer Agency, Research Centre, Vancouver, BC, Canada.
Lo
Maisie
M
Dockery
Peter
P
Mahon
Sarah
S
Karp
Cristina M
CM
Buckley
Arthur R
AR
Lam
Stephen
S
Gout
Peter W
PW
Wang
Yu-Zhuo
YZ
D027182:Amino Acid Transport System y+ / Q000187:drug effects*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001692:Biological Transport; D018288:Carcinoma, Small Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D003553:Cystine / Q000378:metabolism; D016503:Drug Delivery Systems; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005978:Glutathione / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D012970:Sodium Glutamate / Q000494:pharmacology; D012460:Sulfasalazine / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
D027182:Amino Acid Transport System y+; D000894:Anti-Inflammatory Agents, Non-Steroidal; C118895:SLC7A11 protein, human; D012460:Sulfasalazine; D003553:Cystine; D005978:Glutathione; D012970:Sodium Glutamate