Dosing Time-Dependent Changes in the Anti-tumor Effect of xCT Inhibitor Erastin in Human Breast Cancer Xenograft Mice

Shoya Shiromizu, Tomoaki Yamauchi, Naoki Kusunose, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo

Research output: Contribution to journalArticle

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Abstract

Growth of cancer cells is more highly dependent on various types of amino acids than that of normal cells, and thus prevention of amino acid requirement has been recognized as strategies for cancer therapies. In this study, we found that deprivation of cysteine (Cys) in culturing media prevented the growth of various types of human cancer cell lines. Cys is easily converted to cystine (Cys–Cys) in media and uptaken into cells by cystine/glutamate transporter (xCT). The incorporated Cys–Cys is decomposed into Cys, and used for synthesis of glutathione that suppresses reactive oxygen species-induced cell damage. Therefore, we examined whether a selective xCT inhibitor erastin prevented the growth of human cancer cell lines. As a result, erastin significantly prevented the proliferation of various types of human cancer cells. Among them, MDA-MB-231 breast cancer cells were identified as the most erastin-sensitive cells. To investigate the ability of erastin to prevent growth of tumor in mice, MDA-MB-231 breast cancer cells were implanted into BALB/c nude female mice kept under standardized light/dark cycle conditions. The growth of tumor implanted in mice was significantly suppressed by administration of erastin during the light phase, whereas its administration during the dark phase failed to suppress the tumor growth. The dosing time-dependency of erastin-induced cystine/ cysteine deprivation was closely related to that of its anti-tumor effects. Our present findings suggest that the anti-tumor efficacy of erastin in tumor-bearing mice is improved by optimizing the dosing schedule.

Original languageEnglish
Pages (from-to)1921-1925
Number of pages5
JournalBiological and Pharmaceutical Bulletin
Volume42
Issue number11
DOIs
Publication statusPublished - Jan 1 2019

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Heterografts
Breast Neoplasms
Neoplasms
Cysteine
Cystine
Growth
erastin
Amino Acid Transport System X-AG
Amino Acids
Cell Line
Photoperiod
Nude Mice
Glutathione
Reactive Oxygen Species
Appointments and Schedules
Light

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmaceutical Science

Cite this

Dosing Time-Dependent Changes in the Anti-tumor Effect of xCT Inhibitor Erastin in Human Breast Cancer Xenograft Mice. / Shiromizu, Shoya; Yamauchi, Tomoaki; Kusunose, Naoki; Matsunaga, Naoya; Koyanagi, Satoru; Ohdo, Shigehiro.

In: Biological and Pharmaceutical Bulletin, Vol. 42, No. 11, 01.01.2019, p. 1921-1925.

Research output: Contribution to journalArticle

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