Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)

Kohei Shitara, Toshihiko Doi, Osamu Nagano, Chiyo K. Imamura, Takeshi Ozeki, Yuya Ishii, Kenji Tsuchihashi, Shunji Takahashi, Takako E. Nakajima, Shuichi Hironaka, Miki Fukutani, Hiromi Hasegawa, Shogo Nomura, Akihiro Sato, Yasuaki Einaga, Takeshi Kuwata, Hideyuki Saya, Atsushi Ohtsu

Research output: Contribution to journalArticle

30 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)341-349
Number of pages9
JournalGastric Cancer
Volume20
Issue number2
DOIs
Publication statusPublished - Mar 1 2017

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Sulfasalazine
Neoplastic Stem Cells
Stomach Neoplasms
Biopsy
Oxidative Stress
Neoplasms
Maximum Tolerated Dose
Population
Glutathione
Oral Administration
Safety
Survival

All Science Journal Classification (ASJC) codes

  • Oncology
  • Gastroenterology
  • Cancer Research

Cite this

Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). / Shitara, Kohei; Doi, Toshihiko; Nagano, Osamu; Imamura, Chiyo K.; Ozeki, Takeshi; Ishii, Yuya; Tsuchihashi, Kenji; Takahashi, Shunji; Nakajima, Takako E.; Hironaka, Shuichi; Fukutani, Miki; Hasegawa, Hiromi; Nomura, Shogo; Sato, Akihiro; Einaga, Yasuaki; Kuwata, Takeshi; Saya, Hideyuki; Ohtsu, Atsushi.

In: Gastric Cancer, Vol. 20, No. 2, 01.03.2017, p. 341-349.

Research output: Contribution to journalArticle

Shitara, K, Doi, T, Nagano, O, Imamura, CK, Ozeki, T, Ishii, Y, Tsuchihashi, K, Takahashi, S, Nakajima, TE, Hironaka, S, Fukutani, M, Hasegawa, H, Nomura, S, Sato, A, Einaga, Y, Kuwata, T, Saya, H & Ohtsu, A 2017, 'Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)', Gastric Cancer, vol. 20, no. 2, pp. 341-349. https://doi.org/10.1007/s10120-016-0610-8
Shitara, Kohei ; Doi, Toshihiko ; Nagano, Osamu ; Imamura, Chiyo K. ; Ozeki, Takeshi ; Ishii, Yuya ; Tsuchihashi, Kenji ; Takahashi, Shunji ; Nakajima, Takako E. ; Hironaka, Shuichi ; Fukutani, Miki ; Hasegawa, Hiromi ; Nomura, Shogo ; Sato, Akihiro ; Einaga, Yasuaki ; Kuwata, Takeshi ; Saya, Hideyuki ; Ohtsu, Atsushi. / Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205). In: Gastric Cancer. 2017 ; Vol. 20, No. 2. pp. 341-349.
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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.",
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T1 - Dose-escalation study for the targeting of CD44v+ cancer stem cells by sulfasalazine in patients with advanced gastric cancer (EPOC1205)

AU - Shitara, Kohei

AU - Doi, Toshihiko

AU - Nagano, Osamu

AU - Imamura, Chiyo K.

AU - Ozeki, Takeshi

AU - Ishii, Yuya

AU - Tsuchihashi, Kenji

AU - Takahashi, Shunji

AU - Nakajima, Takako E.

AU - Hironaka, Shuichi

AU - Fukutani, Miki

AU - Hasegawa, Hiromi

AU - Nomura, Shogo

AU - Sato, Akihiro

AU - Einaga, Yasuaki

AU - Kuwata, Takeshi

AU - Saya, Hideyuki

AU - Ohtsu, Atsushi

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

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