6-Methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3- c]pyridin-4(5H)-one (FMPPP) exhibits anti-proliferative effect on prostate cancer via autophagy induction and mTOR/p70S6K inhibition
Abstract
Purpose: To investigate 6-methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-c]pyridin-4(5H)-one (FMPPP) as anti-proliferative agent against prostate cancers.
Methods: The FMPPP-mediated changes in cell proliferation were measured using cell counting kit-8 (CCK-8). Flow cytometry and propidium iodide staining were used for cellular DNA content determination. Proteins expression in cells was probed by western blotting assay.
Results: A significant (p < 0.05) dose-dependent suppression of DU145 and PC 3 cell proliferation was observed following FMPPP treatment. FMPPP treatment at 20 μM raised DU145 cell fraction to 75.08 ± 4.87 % in G1 phase when compared to 48.32 ± 3.44 % for control. The population of PC 3 cells in G1- phase reached to 72.78 ± 5.21 % on treatment with 20 μM FMPPP compared to 49.65 ± 4.62 % in control. The FMPPP treatment of DU145 and PC-3 cells elevated LC3-II expression and suppressed SQSTM1/p62 expression. In FMPPP-treated DU145 and PC-3 cells, p-ERK1/2 level was promoted whereas mTOR and p70S6K phosphorylation significantly decreased. Exposure to U0126 (ERK pathway inhibitor) reduced FMPPP-induced increase of LC3-II expression and promotion of p-ERK1/2 level in DU145 and PC-3 cells.
Conclusion: FMPPP exhibits anti-proliferative effect by increasing autophagy in prostate cancer cells. The cytotoxicity of FMPPP involves elevation of ERK1/2 phosphorylation and targeting mTOR pathway in DU145 and PC-3 cells. Therefore, FMPPP may be beneficial for the treatment of prostate cancer in patients.
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