FTY720 shows promising in vitro and in vivo preclinical activity by downmodulating Cyclin D1 and phospho-Akt in mantle cell lymphoma.
OBJECTIVE
Despite the progress that has been made in the treatment of mantle cell lymphoma (MCL), all patients invariably relapse with the currently available therapies. Because of the absence of curative therapy for MCL, we explored FTY720 as a novel agent against MCL.


METHODS
The cytotoxic effect of FTY720 in primary MCL tumor cells and cell lines were evaluated in vitro. The effects of FTY720 on caspase activation, generation of reactive oxygen species, and modulation of Cyclin D1 and Akt, which are implied in the pathogenesis of MCL, were investigated. The in vivo efficacy of FTY720 was evaluated in a Jeko-severe combined immunodeficient xenograft model of human MCL.


RESULTS
FTY720 mediated time- and dose-dependent cytotoxicity in primary MCL tumor cells and MCL cell lines in vitro. FTY720-induced cytotoxicity occured independent of caspase activation but dependent on the generation of ROS in MCL. In addition, FTY720 treatment resulted in the time-dependent downmodulation of Cyclin D1 and accumulation of cells in G(0)-G(1) and G(2)-M phases of the cell cycle with concomitant decrease in S-phase entry. Furthermore, concentrations of FTY720 that induced cytotoxicity led to decreased phospho-Akt in primary MCL cells and cell lines. Most importantly, the in vivo therapeutic activity of FTY720 was shown in severe combined immunodeficient mice engrafted with the Jeko MCL cell line.


CONCLUSIONS
These results provide the first evidence for a potential use of FTY720 in targeting key pathways that are operable in the pathogenesis of MCL and warrant further investigation of FTY720 in clinical trials to treat patients with MCL.
Liu
Qing
Q
Division of Pharmaceutics, College of Pharmacy, the Ohio State University, Columbus, Ohio 43210, USA.
Alinari
Lapo
L
Chen
Ching-Shih
CS
Yan
Fengting
F
Dalton
James T
JT
Lapalombella
Rosa
R
Zhang
Xiaoli
X
Mani
Rajeswaran
R
Lin
Teresa
T
Byrd
John C
JC
Baiocchi
Robert A
RA
Muthusamy
Natarajan
N
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism*; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D011409:Propylene Glycols / Q000627:therapeutic use*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011409:Propylene Glycols; D017382:Reactive Oxygen Species; D019938:Cyclin D1; D051057:Proto-Oncogene Proteins c-akt; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine
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