FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft

Takanobu Ubai, Haruhito Azuma, Yatsugu Kotake, Teruo Inamoto, Kiyoshi Takahara, Yuko Ito, Satoshi Kiyama, Takeshi Sakamoto, Shigeo Horie, Satoru Muto, Shiro Takahara, Yoshinori Otsuki, Yoji Katsuoka

Research output: Contribution to journalArticle

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Abstract

Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 μM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.

Original languageEnglish
Pages (from-to)75-88
Number of pages14
JournalAnticancer research
Volume27
Issue number1 A
Publication statusPublished - 01-01-2007

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Renal Cell Carcinoma
Heterografts
Apoptosis
Growth
Neoplasms
Cisplatin
Kidney Neoplasms
In Vitro Techniques
Fingolimod Hydrochloride
Extracellular Signal-Regulated MAP Kinases
In Situ Nick-End Labeling
Immunosuppressive Agents
Chromatin
Electrophoresis
Real-Time Polymerase Chain Reaction
Signal Transduction
Electron Microscopy
Flow Cytometry
Western Blotting
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Ubai, Takanobu ; Azuma, Haruhito ; Kotake, Yatsugu ; Inamoto, Teruo ; Takahara, Kiyoshi ; Ito, Yuko ; Kiyama, Satoshi ; Sakamoto, Takeshi ; Horie, Shigeo ; Muto, Satoru ; Takahara, Shiro ; Otsuki, Yoshinori ; Katsuoka, Yoji. / FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft. In: Anticancer research. 2007 ; Vol. 27, No. 1 A. pp. 75-88.
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title = "FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft",
abstract = "Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 μM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.",
author = "Takanobu Ubai and Haruhito Azuma and Yatsugu Kotake and Teruo Inamoto and Kiyoshi Takahara and Yuko Ito and Satoshi Kiyama and Takeshi Sakamoto and Shigeo Horie and Satoru Muto and Shiro Takahara and Yoshinori Otsuki and Yoji Katsuoka",
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Ubai, T, Azuma, H, Kotake, Y, Inamoto, T, Takahara, K, Ito, Y, Kiyama, S, Sakamoto, T, Horie, S, Muto, S, Takahara, S, Otsuki, Y & Katsuoka, Y 2007, 'FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft', Anticancer research, vol. 27, no. 1 A, pp. 75-88.

FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft. / Ubai, Takanobu; Azuma, Haruhito; Kotake, Yatsugu; Inamoto, Teruo; Takahara, Kiyoshi; Ito, Yuko; Kiyama, Satoshi; Sakamoto, Takeshi; Horie, Shigeo; Muto, Satoru; Takahara, Shiro; Otsuki, Yoshinori; Katsuoka, Yoji.

In: Anticancer research, Vol. 27, No. 1 A, 01.01.2007, p. 75-88.

Research output: Contribution to journalArticle

TY - JOUR

T1 - FTY720 induced Bcl-associated and Fas-independent apoptosis in human renal cancer cells in vitro and significantly reduced in vivo tumor growth in mouse xenograft

AU - Ubai, Takanobu

AU - Azuma, Haruhito

AU - Kotake, Yatsugu

AU - Inamoto, Teruo

AU - Takahara, Kiyoshi

AU - Ito, Yuko

AU - Kiyama, Satoshi

AU - Sakamoto, Takeshi

AU - Horie, Shigeo

AU - Muto, Satoru

AU - Takahara, Shiro

AU - Otsuki, Yoshinori

AU - Katsuoka, Yoji

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 μM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.

AB - Background: A unique immunosuppressant, FTY720, selectively induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. The potential that this unique mechanism could provide anticancer potential by inducing apoptosis in the human renal cancer cell line, ACHN, which is resistant to cisplatin, and its molecular pathway was investigated. Materials and Methods: The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and flow cytometry. Apoptosis assay, including TUNEL staining, electron microscopy and DNA electrophoresis, was performed and the molecular pathway of FTY720 was evaluated by real time RT-PCR and Western blot. The in vivo effect of FTY720 was evaluated using a murine zenograft model. Results: The susceptibility to FTY720 was significantly higher in ACHN cancer cells than in normal renal tubular cells (HK-2) at a concentration of less than 30 μM, while the susceptibility to cisplatin was even higher in HK-2 than in ACHN. Cancer cells treated with FTY720 showed findings typical of apoptosis with highly condensed nuclear chromatin and fragmented nuclei. The molecular analysis revealed that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway, and that inhibition of extracellular signal-regulated kinase (ERK) activity was involved in its underlying mechanism of action. FTY720 treatment significantly prevented in vivo tumor growth without any severe adverse reactions, while cisplatin treatment did not inhibit tumor growth despite exhibiting severe side-effects. Conclusion: FTY720 may be a promising candidate for a new anticancer therapy of renal cancer.

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