Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation

Wang, Jing-Ding; Takahara, Shiro; Nonomura, Norio; Ichimaru, Naotsugu; Toki, Kiyohide; Azuma, Haruhito; Matsumiya, Kiyomi; Okuyama, Äkïhïko; Suzuki, Seiichi

doi:10.1002/(sici)1097-0045(19990615)40:1<50::aid-pros6>3.0.co;2-n

Cited by 69 publications

(56 citation statements)

References 14 publications

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“…This activation preceded FTY720-induced nuclear DNA fragmentation, indicating that caspase-3 is involved in FTY720-induced apoptosis. Recent studies by Wang et al have revealed that caspase-3 is activated by FTY720 in the prostate cancer cell line, DU145, indicating that caspase-3 activation in FTY720-induced apoptosis is not cell specific (53). In addition, the pan-caspase inhibitor, Z-VAD-FMK, completely blocked subsequent FTY720-induced nuclear DNA fragmentation in this study.…”

Section: Discussionsupporting

confidence: 59%

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

Nagahara

Ikekita

Shinomiya³

2000

The Journal of Immunology

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FTY720 has immunosuppressive activity in experimental organ transplantation and shows a prompt and protracted decrease of blood T lymphocytes upon oral administration. The blood lymphocyte decrease in vivo was mainly a result of FTY720-induced apoptosis. However, this apoptotic mechanism is not well understood. We examined the mechanism of FTY720-induced apoptosis in lymphoma. Western blotting and fluorescent caspase-specific substrate revealed that caspase-3 is involved in FTY720-induced apoptosis, whereas caspase-1 is not. Apoptotic cell death was inhibited by the pan-caspase inhibitor, Z-VAD-FMK, suggesting that caspase activation is essential for FTY720-induced apoptosis. FTY720 reduced mitochondrial transmembrane potential and released cytochrome c from the mitochondria of intact cells as well as in a cell-free system even in the presence of Z-VAD-FMK. As these mitochondrial reactions occurred before caspase activation, we concluded that FTY720 directly influences mitochondrial functions. The inhibition of mitochondrial permeability transition by Bcl-2 overexpression or by chemical inhibitors prevented all apoptotic events occurring in intact cells and in a cell-free system. Moreover, using a cell-free system, FTY720 did not directly affect isolated nuclei or cytosol. These results indicate that FTY720 directly affects mitochondria and triggers permeability transition to induce further apoptotic events.

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Section: Discussionsupporting

confidence: 59%

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

Nagahara

Ikekita

Shinomiya³

2000

The Journal of Immunology

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“…This observation led to investigations into the potential of FTY720 to act as an apoptosis-inducing anticancer agent (8). FTY720 was first reported to induce early apoptosis in an androgen-independent prostate cancer cell line dependent on caspase-3 activation (16). Subsequently, it demonstrated preclinical antitumor efficacy in various cancer models.…”

Section: Anticancer Effects Of Fty720mentioning

confidence: 99%

FTY720 for cancer therapy (Review)

Zhang

Wang

et al. 2013

Oncology Reports

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Abstract. 2-Amino-2-[2-(4-octylphenyl)]-1,3-propanediol hydrochloride (FTY720) is a potent immunosuppressant which has been approved by the Food and Drug Administration (FDA) as a new treatment for multiple sclerosis. As an immunosuppressant, it displays its anti-multiple sclerosis, immunosuppressive effects by activating sphingosine-1-phosphate receptors (S1PRs). In addition to the immunosuppressive effects, FTY720 also shows preclinical antitumor efficacy in several cancer models. In most cases, phosphorylation of FTY720 is not required for its cytotoxic effect, indicating the involvement of S1PR-independent mechanisms which are starkly different from the immunosuppressive property of FTY720. In the present study, we reviewed the rapidly advancing field of FTY720 in cancer therapy as well as some molecular targets of the unphosphorylated form of FTY720.

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“…9 FTY720 is a sphingosine analog and a potent immunosuppressive drug currently approved for treating multiple sclerosis. 10,11 Moreover, FTY720 has also been shown to induce apoptosis in multiple myeloma, 12 prostate, 13 breast, 14 kidney, 15 and bladder cancer cells. 16 Based on this experimental evidence, we sought to analyze the radiosensitizing effects of FTY720 in human breast cancer cells, in order to clearly assess its effect on growth, proliferation, and apoptosis.…”

Section: Introductionmentioning

confidence: 99%

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

Marvaso

Barone

Amodio

et al. 2014

Cancer Biology & Therapy

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Radiotherapy is one of the most effective therapeutic strategies for breast cancer patients, although its efficacy may be reduced by intrinsic radiation resistance of cancer cells. Recent investigations demonstrate a link between cancer cell radio-resistance and activation of sphingosine kinase (SphK1), which plays a key role in the balance of lipid signaling molecules. Sphingosine kinase (SphK1) activity can alter the sphingosine-1-phosphate (S1P)/ceramide ratio leading to an imbalance in the sphingolipid rheostat. Fingolimod (FTY720) is a novel sphingosine analog and a potent immunosuppressive drug that acts as a SphK1 antagonist, inhibits the growth, and induces apoptosis in different human cancer cell lines. We sought to investigate the in vitro radiosensitizing effects of FTY720 on the MDA-MB-361 breast cancer cell line and to assess the effects elicited by radiation and FTY720 combined treatments. We found that FTY720 significantly increased anti-proliferative and pro-apoptotic effects induced by a single dose of ionizing radiation while causing autophagosome accumulation. At the molecular level, FTY720 significantly potentiated radiation effects on perturbation of signaling pathways involved in regulation of cell cycle and apoptosis, such as PI3K/AKT and MAPK. In conclusion, our data highlight a potent radiosensitizing effect of FTY720 on breast cancer cells and provide the basis of novel therapeutic strategies for breast cancer treatment

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Early induction of apoptosis in androgen-independent prostate cancer cell line by FTY720 requires caspase-3 activation

Cited by 69 publications

References 14 publications

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

Immunosuppressant FTY720 Induces Apoptosis by Direct Induction of Permeability Transition and Release of Cytochrome c from Mitochondria

FTY720 for cancer therapy (Review)

Sphingosine analog fingolimod (FTY720) increases radiation sensitivity of human breast cancer cells in vitro

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