FTY720 is a unique
immunosuppressive agent that exerts its activity by inducing apoptosis in lymphocytes. We conducted the present study to investigate the effects of
FTY720 on
cancer growth and
metastasis, as well as its mechanism of action. In vitro treatment with
FTY720 induced dramatic
cancer cell apoptosis in a mouse
breast cancer cell line, JygMC(A). Electron microscopy revealed distinct changes on the cell surface with decreased filopodias and microvilli in
cancer cells treated with
FTY720 at 2 microM and clear evidence of apoptosis
at 10 microM. Interestingly, the effect of
FTY720 was significantly less in the normal fibroblasts than in the
cancer cells, indicating greater susceptibility of
cancer cells to the agent. We then tested the in vivo effect of
FTY720 in a mouse
breast cancer model created by inoculating JygMC(A) cells (s.c.) in the flank region of BALB/c-nu/nu mice at three different dosages (2, 5, and 10 mg/kg/day;
n = 30/group).
Tumor growth was markedly suppressed at a dosage of 5 mg/kg or more without notable side effects. In addition,
tumor metastasis, which was dramatically evident in control mice, was significantly prevented even at a low dose (2 mg/kg/day), resulting in a significant prolongation of animal survival. These data led us to additionally investigate the mechanism of action, especially the prevention of
metastasis at a low dose.
FTY720 treatment at 2 microM caused a remarkable cytoskeletal change with deformed and decreased filopodias in
cancer cells. In addition, it significantly decreased the ability of
cancer cells to adhere and migrate to extracellular matrix components, and markedly reduced the expression of
integrins on the
cancer cell surface. These results indicate that
FTY720 is a potent
anticancer agent that induces
cancer cell apoptosis and is markedly effective for prevention of
metastasis. The changes of cellular structure with reduction of
integrin expression may be one of its underlying mechanisms of action.