Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer

Koichiro Ogihara, Eiji Kikuchi, Shogo Okazaki, Masayuki Hagiwara, Toshikazu Takeda, Kazuhiro Matsumoto, Takeo Kosaka, Shuji Mikami, Hideyuki Saya, Mototsugu Oya

Research output: Contribution to journalArticle

Abstract

The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9-xCT system in order to enhance cisplatin (CDDP)-induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer-specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho-p38 MAPK protein expression by SSZ with or without CDDP were assessed in MBT-2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT-2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT-2V cells by inhibiting CD44v9 expression and upregulating phospho-p38 MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT-2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.

Original languageEnglish
Pages (from-to)1431-1441
Number of pages11
JournalCancer Science
Volume110
Issue number4
DOIs
Publication statusPublished - 2019 Apr 1

Fingerprint

Sulfasalazine
Urinary Bladder Neoplasms
Cisplatin
p38 Mitogen-Activated Protein Kinases
Muscles
Lung
Glutathione
Reactive Oxygen Species
Neoplastic Stem Cells
Cystectomy
Neoplasms
Protein Isoforms
Proteins
Biomarkers
Recurrence

Keywords

  • bladder cancer
  • CD44v9
  • cisplatin
  • metastasis
  • sulfasalazine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer. / Ogihara, Koichiro; Kikuchi, Eiji; Okazaki, Shogo; Hagiwara, Masayuki; Takeda, Toshikazu; Matsumoto, Kazuhiro; Kosaka, Takeo; Mikami, Shuji; Saya, Hideyuki; Oya, Mototsugu.

In: Cancer Science, Vol. 110, No. 4, 01.04.2019, p. 1431-1441.

Research output: Contribution to journalArticle

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