Kohei Shitara1, Toshihiko Doi2,3, Osamu Nagano4, Chiyo K Imamura5, Takeshi Ozeki6, Yuya Ishii7, Kenji Tsuchihashi4, Shunji Takahashi8, Takako E Nakajima9, Shuichi Hironaka10, Miki Fukutani11, Hiromi Hasegawa11, Shogo Nomura11, Akihiro Sato11, Yasuaki Einaga7, Takeshi Kuwata12, Hideyuki Saya13, Atsushi Ohtsu11. 1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 2. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp. 3. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. tdoi@east.ncc.go.jp. 4. Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. 5. Department of Clinical Pharmacokinetics and Pharmacodynamics, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. 6. Laboratory for Pharmacogenomics, RIKEN Center for Integrative Medical Sciences, 1-7-22 Suehiro-cho, Tsurumi-ku, Yokohama, Kanagawa, 230-0045, Japan. 7. Department of Chemistry, Faculty of Science and Technology, Keio University, Hiyoshi, Yokohama, 223-8522, Japan. 8. Medical Oncology, The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto, Tokyo, 135-8550, Japan. 9. Department of Medical Oncology, St. Marianna University School of Medicine, 2-16-1 Sugao, Miyamae, Kawasaki, Kanagawa, 216-8511, Japan. 10. Clinical Trial Promotion Department, Chiba Cancer Center, 666-2 Nitonacho, Chuo-ku, Chiba, Chiba, 260-8717, Japan. 11. Exploratory Oncology Research and Clinical Trial Center, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 12. Division of Pathology, Research Center for Innovative Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan. 13. Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. hsaya@a5.keio.jp.
Abstract
BACKGROUND: Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted. METHODS: SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH. RESULTS: Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater. CONCLUSIONS: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.
BACKGROUND:Cancer stem cells (CSCs) have enhanced mechanisms of protection from oxidative stress. A variant form of CD44 (CD44v), a major CSC marker, was shown to interact with xCT, a subunit of cystine-glutamate transporter, which maintains high levels of intracellular reduced glutathione (GSH) which defend the cell against oxidative stress. Sulfasalazine (SSZ) is an inhibitor of xCT and was shown to suppress the survival of CD44v-positive stem-like cancer cells both in vitro and in vivo. To find the dose of SSZ which can safely reduce the population of CD44v-positive cells in tumors, a dose-escalation study in patients with advanced gastric cancer was conducted. METHODS:SSZ was given four times daily by oral administration with 2 weeks as one cycle. Tumor biopsies were obtained before and after 14 days of administration of SSZ to evaluate expression of CD44v and the intratumoral level of GSH. RESULTS: Eleven patients were enrolled and received a dosage from 8 to 12 g/day. Safety was confirmed up to a dosage of 12 g/day, which was considered the maximum tolerated dose. Among the eight patients with CD44v-positive cells in their pretreatment biopsy samples, the CD44v-positive cancer cell population appeared to be reduced in the posttreatment biopsy tissues of four patients. Intratumoral GSH levels were also decreased in two patients, suggesting biological effectiveness of SSZ at 8 g/day or greater. CONCLUSIONS: This is the first study of SSZ as an xCT inhibitor for targeting CSCs. Reduction of the levels of CD44v-positive cells and GSH was observed in some patients, consistent with the mode of action of SSZ in CSCs.
Authors: Wen Min Lau; Eileen Teng; Hui Shan Chong; Kirsten Anne Pagaduan Lopez; Amy Yuh Ling Tay; Manuel Salto-Tellez; Asim Shabbir; Jimmy Bok Yan So; Shing Leng Chan Journal: Cancer Res Date: 2014-03-11 Impact factor: 12.701
Authors: K Hirata; H Suzuki; H Imaeda; J Matsuzaki; H Tsugawa; O Nagano; K Asakura; H Saya; T Hibi Journal: Br J Cancer Date: 2013-06-18 Impact factor: 7.640
Authors: Lise Verbruggen; Lindsay Sprimont; Eduard Bentea; Pauline Janssen; Azzedine Gharib; Lauren Deneyer; Laura De Pauw; Olaya Lara; Hideyo Sato; Charles Nicaise; Ann Massie Journal: Front Pharmacol Date: 2021-05-18 Impact factor: 5.810