Downregulation of cystine transporter xc by irinotecan in human head and neck cancer FaDu xenografts.
BACKGROUND
The purpose of this study was: (1) to document the critical requirement of cystine for growth of human tumor cells in vitro, and (2) to determine the effect of the anticancer agent irinotecan on the cystine transporter x(c)(-) in head and neck FaDu xenografts.


METHODS
Cell growth was measured by sulforhodamine B assay. xCT protein, glutathione (GSH) and DNA damage were determined using Western blot, spectrophotometry, and immunohistochemistry, respectively.


RESULTS
Depletion of cystine from the medium inhibited tumor cell growth. Treatment of FaDu tumor with a therapeutic dose of irinotecan resulted in depression of xCT protein levels, leading to tumor growth retardation and downregulation of GSH with increased reactive oxygen species (ROS). The accumulation of ROS correlated with increased DNA damage as evidenced by increased H2AX.


CONCLUSIONS
Depression of xCT protein by irinotecan resulted in downregulation of GSH and increase in ROS, which could be the other possible mechanisms of DNA damage by irinotecan.
Chintala
Sreenivasulu
S
Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA. sreenivasulu.chintala@roswellpark.org
Tóth
Károly
K
Yin
Ming-Biao
MB
Bhattacharya
Arup
A
Smith
Sylvia B
SB
Ola
M Shamsul
MS
Cao
Shousong
S
Durrani
Farukh A
FA
Zinia
Tanjima R
TR
Dean
Rebecca
R
Slocum
Harry K
HK
Rustum
Youcef M
YM
D026905:Amino Acid Transport Systems / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D000818:Animals; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D045744:Cell Line, Tumor; D003553:Cystine / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D006258:Head and Neck Neoplasms / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D023041:Xenograft Model Antitumor Assays / Q000379:methods
D026905:Amino Acid Transport Systems; D003553:Cystine; D000077146:Irinotecan; D002166:Camptothecin