FTY720 induces apoptosis in multiple myeloma cells and overcomes drug resistance.
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 (DeltaPsim) 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 alpha-induced IkappaBalpha and nuclear factor-kappaB 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.
Yasui
Hiroshi
H
Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Hideshima
Teru
T
Raje
Noopur
N
Roccaro
Aldo M
AM
Shiraishi
Norihiko
N
Kumar
Shaji
S
Hamasaki
Makoto
M
Ishitsuka
Kenji
K
Tai
Yu-Tzu
YT
Podar
Klaus
K
Catley
Laurence
L
Mitsiades
Constantine S
CS
Richardson
Paul G
PG
Albert
Rainer
R
Brinkmann
Volker
V
Chauhan
Dharminder
D
Anderson
Kenneth C
KC
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001854:Bone Marrow Cells / Q000166:cytology; D020169:Caspases / Q000378:metabolism; D048708:Cell Growth Processes / Q000502:physiology; D018920:Coculture Techniques; D019008:Drug Resistance, Neoplasm; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000473:pathology; D011409:Propylene Glycols / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives; D017154:Stromal Cells / Q000166:cytology; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; D007166:Immunosuppressive Agents; D015850:Interleukin-6; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; D020169:Caspases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine