PPAR Gamma Activators: Off-Target Against Glioma Cell Migration and Brain Invasion
Figure 1
Troglitazone (TRO) and the PPARγ inactive Δ2-troglitazone (Δ2-TRO) reduce
glioma cell viability and TGF- release. Δ2-TRO was synthesized as previously described in [11]. (a), (c) Concentration-dependent
inhibition of glioma cell viability by TRO (a) or Δ2-TRO (c) in the
indicated cell lines are given as mean ± SEM percentage relative to time- and
solvent-matched controls. Cell viability assays (MTT
assay, 96 hours) were performed as described earlier [12, 13]. Inhibitory
concentrations I and I, defined as concentrations
shown to inhibit tumor cell viability by 50% or 90%,
respectively, were determined by nonlinear regression data analysis: TRO: F98 (62 M, 166 M), SMA-560 (26 M, 407 M), U-87 MG (120 M, 324 M), and U-373 MG (123 M,
331 M); Δ2-TRO: F98 (46 M, 95 M), SMA-560 (23 M, 93 M), U-87 MG (78 M, 132 M), and U-373 MG (71 M, 126 M). Troglitazone and the PPARγ inactive Δ2-troglitazone
reduce TGF- release at low micromolar doses: (b), (d) quantification
of TGF- release by F98, SMA-560, U87-MG, and U-373 MG glioma cell
culture supernatants following TRO (b)
or Δ2-TRO (d) treatment for 48 hours. TGF- protein levels in glioma cell culture supernatants were determined as described
in [9] using the mouse/rat/porcine/canine or the human quantikine
TGF- ELISA Kit (R&D Systems, Minneapolis, Minn, USA), respectively. Each
experiment was repeated at least 3 times (). Drug concentrations shown
to inhibit TGF- release by 50% or 90%, respectively, were
determined by nonlinear regression data analysis: TRO: F98 (7 M, 11 M),
SMA-560 (8 M, 15 M), U-87 MG (8 M, 28 M), and U-373 MG (10 M, 30 M); Δ2-TRO:F98 (3 M, 5 M), SMA-560
(3 M, 8 M), U-87 MG (4 M, 14 M), and U-373 MG (4 M, 14 M). Δ2-Troglitazone
displays higher potencies than troglitazone. Using I concentrations
of Δ2-TRO and equimolar concentrations of TRO,
the PPARγ inactive Δ2-TRO displays a significantly stronger
effect in both experimental paradigms (*** = , -test) (e), (f).
