FTY720 demonstrates promising preclinical activity for chronic lymphocytic leukemia and lymphoblastic leukemia/lymphoma.
FTY720 is an immunosuppressant developed to prevent organ transplant rejection. Recent studies indicate an additional role for FTY720 in inducing cell apoptosis. We demonstrate here that FTY720 mediates toxic effects in cell lines representing different B-cell malignancies and primary B cells from patients with chronic lymphocytic leukemia (CLL). In contrast to previous reports in T-cell lines, FTY720-induced toxicity in the Raji cell line and primary CLL B cells is independent of activation of caspases or poly(ADP-ribose) polymerase processing. Further, pancaspase inhibitor Z-VAD-fmk failed to rescue these cells from apoptosis mediated by FTY720. FTY720 induced down-regulation of Mcl-1 but not Bcl-2 in CLL B cells. Overexpression of Bcl-2 failed to protect transformed B cells from FTY720-induced apoptosis, suggesting a Bcl-2-independent mechanism. Interestingly, FTY720 induced protein phosphatase 2a (PP2a) activation and downstream dephosphorylation of ERK1/2, whereas okadaic acid at concentrations that inhibited the FTY720-induced PP2a activation also resulted in inhibition of FTY720-mediated apoptosis and restoration of baseline ERK1/2 phosphorylation in primary CLL cells, indicating a role for PP2a activation in FTY720-induced cytotoxicity. Further, FTY720 treatment resulted in significant prolonged survival in a xenograft severe combined immunodeficiency (SCID) mouse model of disseminated B-cell lymphoma/leukemia. These results provide the first evidence for the potential use of FTY720 as a therapeutic agent in a variety of B-cell malignancies, including CLL.
Liu
Qing
Q
Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Zhao
Xiaobin
X
Frissora
Frank
F
Ma
Yihui
Y
Santhanam
Ramasamy
R
Jarjoura
David
D
Lehman
Amy
A
Perrotti
Danilo
D
Chen
Ching-Shih
CS
Dalton
James T
JT
Muthusamy
Natarajan
N
Byrd
John C
JC
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000633:toxicity*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011409:Propylene Glycols / Q000633:toxicity*; D054648:Protein Phosphatase 2 / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D023041:Xenograft Model Antitumor Assays
D007166:Immunosuppressive Agents; D008246:Lysophospholipids; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; C060506:sphingosine 1-phosphate; D054648:Protein Phosphatase 2; D020169:Caspases; D003546:Cysteine Endopeptidases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine