FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance

Hiroshi Yasui, Teru Hideshima, Noopur Raje, Aldo M. Roccaro, Norihiko Shiraishi, Shaji Kumar, Makoto Hamasaki, Kenji Ishitsuka, Yu Tzu Tai, Klaus Podar, Laurence Catley, Constantine S. Mitsiades, Paul G. Richardson, Rainer Albert, Volker Brinkmann, Dharminder Chauhan, Kenneth C. Anderson

Research output: Contribution to journalArticle

87 Scopus citations

Abstract

The novel immunomodulator FTY720 down-modulates sphingosine-1-phosphate receptor 1 on lymphocytes at low nanomolar concentrations, thereby inhibiting sphingosine-1-phosphate receptor 1-dependent egress of lymphocytes from lymph nodes into efferent lymphatics and blood. At high micromolar concentration, FTY720 has been shown to induce growth inhibition and/or apoptosis in human cancer cells in vitro. In this study, we investigated the biological effects of FTY720 on multiple myeloma cells. We found that FTY720 induces potent cytotoxicity against drug-sensitive and drug-resistant multiple myeloma cell lines as well as freshly isolated tumor cells from multiple myeloma patients who do not respond to conventional agents. FTY720 triggers activation of caspase-8, -9, and -3, followed by poly(ADP-ribose) polymerase cleavage. Interestingly, FTY720 induces alterations in mitochondrial membrane potential (ΔΨm) and Bax cleavage, followed by translocation of cytochrome c and Smac/Diablo from mitochondria to the cytosol. In combination treatment studies, both dexamethasone and anti-Fas antibodies augment anti-multiple myeloma activity induced by FTY720. Neither interleukin-6 nor insulin-like growth factor-I, which both induce multiple myeloma cell growth and abrogate dexamethasone-induced apoptosis, protect against FTY720-induced growth inhibition. Importantly, growth of multiple myeloma cells adherent to bone marrow stromal cells is also significantly inhibited by FTY720. Finally, it down-regulates interleukin-6-induced phosphorylation of Akt, signal transducers and activators of transcription 3, and p42/44 mitogen-activated protein kinase; insulin-like growth factor-I-triggered Akt phosphorylation; and tumor necrosis factor α-induced IκBα and nuclear factor-κB p65 phosphorylation. These results suggest that FTY720 overcomes drug resistance in multiple myeloma cells and provide the rationale for its clinical evaluation to improve patient outcome in multiple myeloma.

Original languageEnglish (US)
Pages (from-to)7478-7484
Number of pages7
JournalCancer research
Volume65
Issue number16
DOIs
StatePublished - Aug 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Yasui, H., Hideshima, T., Raje, N., Roccaro, A. M., Shiraishi, N., Kumar, S., Hamasaki, M., Ishitsuka, K., Tai, Y. T., Podar, K., Catley, L., Mitsiades, C. S., Richardson, P. G., Albert, R., Brinkmann, V., Chauhan, D., & Anderson, K. C. (2005). FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance. Cancer research, 65(16), 7478-7484. https://doi.org/10.1158/0008-5472.CAN-05-0850