Selective cancer cell apoptosis induced by FTY720; evidence for a Bcl-dependent pathway and impairment in ERK activity.
BACKGROUND
FTY720 is a unique immunosuppressant that induces apoptosis in activated lymphocytes, but not in other hematopoietic cells. We conducted the present study to investigate its anticancer effect and molecular pathway in inducing apoptosis using murine breast cancer models.


METHODS
The difference in drug susceptibility to FTY720 between cancer cells and non-cancer cells was examined by MTT assay and cell growth assay. FTY720-induced apoptosis was determined by electron microscopy and DNA electrophoresis, and its molecular pathway was evaluated by Western blot analysis. We then tested in vivo the effect of this agent using two murine breast cancer models.


RESULTS
FTY720 treatment induced selective cancer cell apoptosis in vitro at a concentration of less than 10 microM. In vivo tumor growth was significantly prevented with induction of apoptosis in both models without any severe systemic adverse reactions. The evaluation of intracellular protease activity demonstrated that FTY720-induced apoptosis was mediated by a Fas-independent, Bcl-associated signal transduction pathway. Inhibition of extracellular signal-regulated kinase (ERK) activity may be involved in its underlying mechanism of action.


CONCLUSIONS
FTY720 may be a promising candidate for a new anticancer therapy, which potentially induces selective apoptosis in cancer cells.
Azuma
Haruhito
H
Department of Urology, Osaka Medical College, Takatsuki, Osaka, 569-8686, Japan.
Horie
Shigeo
S
Muto
Satoru
S
Otsuki
Yoshinori
Y
Matsumoto
Kenji
K
Morimoto
Junji
J
Gotoh
Rieko
R
Okuyama
Akihiko
A
Suzuki
Seiichi
S
Katsuoka
Yoji
Y
Takahara
Shiro
S
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D000068876:Fingolimod Hydrochloride; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors; D007166:Immunosuppressive Agents / Q000009:adverse effects / Q000494:pharmacology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011409:Propylene Glycols / Q000009:adverse effects / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494812:Bcl2l1 protein, mouse; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine