Sunitinib enhances antitumor effects against chemotherapy-resistant bladder cancer through suppression of ERK1/2 phosphorylation

Ario Takeuchi, Masatoshi Eto, Masaki Shiota, Katsunori Tatsugami, Akira Yokomizo, Kentaro Kuroiwa, Momoe Itsumi, Seiji Naito

研究成果: Contribution to journalArticle査読

20 被引用数 (Scopus)


Bladder cancer patients who are refractory to chemotherapy have a poor prognosis. Furthermore, additional chemotherapies provide little benefit to patients who have relapsed after an initial response. Recently, it was reported that several molecular pathways are implicated in bladder carcinogenesis, including the epidermal growth factor receptor (EGFR) pathway, the vascular endothelial growth factor (VEGF) pathway and the Ras-MAPK pathway. We hypothesized that sunitinib would be effective in bladder cancer as it is an oral inhibitor of multiple receptor tyrosine kinases, including VEGF receptors, platelet derived growth factor (PDGF) receptors and stem cell factor receptor (c-KIT), and is a standard first-line treatment of advanced clear cell renal carcinoma. In the present study, the antiproliferative effects of sunitinib were clearly demonstrated in KK47, KK47/DDP20 and KK47/ADR cell lines in vitro due to the suppression of ERK1/2 phosphorylation. In a mouse model, the antitumor effects of sunitinib were again clearly seen. Also, treatment with sunitinib decreased the abundance of regulatory T cells (Tregs). However, cytotoxic T lymphocyte (CTL) activity was not induced sufficiently as compared with an IFN-α-treated group. Our results suggested that sunitinib was effective in chemotherapy-resistant bladder cancer patients. On the other hand, these findings provided the rationale for combination therapy with sunitinib and immune-based cancer therapy for advanced malignancies to prevent the occurrence of rebound phenomena.

ジャーナルInternational journal of oncology
出版ステータス出版済み - 5 2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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