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Inhibition on Proteasome β1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells.

Li D, Lu Y, Sun P, Feng LX, Liu M, Hu LH, Wu WY, Jiang BH, Yang M, Qu XB, Guo DA, Liu X - PLoS ONE (2015)

Bottom Line: Moore.Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline.Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Changchun University of Chinese Medicine, Changchun 130117, P.R. China.

ABSTRACT
Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome β1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome β1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC-3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IκB-α were observed in fangchinoline-treated cells. Over-expression of proteasome β1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome β1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit.

No MeSH data available.


Related in: MedlinePlus

Inhibitive effects of fangchinoline on cell proliferation and cellular proteasome activities of PC-3 cells and LnCap cells.(A) Cell viability (MTT assay result) of PC-3 cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. Data were statistical results of three independent experiments. (B) Cellular proteasome activities of PC-3 cells treated with 0.1% DMSO or fangchinoline at different concentrations for 24 h. (C) Cell viability (MTT assay result) of LnCap cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. (D) Cellular proteasome activities of control PC-3 cells treated with 0.1% DMSO (solvent control) or fangchinoline at different concentrations for 24 h. Data were statistical results of three independent experiments. *p<0.05 vs. solvent control. Carfilzomib was used as positive control.
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pone.0141681.g002: Inhibitive effects of fangchinoline on cell proliferation and cellular proteasome activities of PC-3 cells and LnCap cells.(A) Cell viability (MTT assay result) of PC-3 cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. Data were statistical results of three independent experiments. (B) Cellular proteasome activities of PC-3 cells treated with 0.1% DMSO or fangchinoline at different concentrations for 24 h. (C) Cell viability (MTT assay result) of LnCap cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. (D) Cellular proteasome activities of control PC-3 cells treated with 0.1% DMSO (solvent control) or fangchinoline at different concentrations for 24 h. Data were statistical results of three independent experiments. *p<0.05 vs. solvent control. Carfilzomib was used as positive control.

Mentions: As shown in Fig 2A, fangchinoline could dose-dependently and time-dependently decrease the viability of PC-3 cells. The IC50 values of fangchinoline in inhibiting cell proliferation of PC-3 cells were 27.53±3.346 μM for 24 h, 13.13±1.579 μM for 48 h, and 7.247±0.3122 μM for 72 h treatment, respectively. Furthermore, as shown in Fig 2B, fangchinoline could dose-dependently inhibit the C-L activity of cellular proteasome, which was mediated by proteasome β1 subunit. The inhibition on C-L activity was significant at doses of 1 and 10 μM fangchinoline. The activities of proteasome trypsin-like (T-L) and chymotrypsin-like (CT-L) activities, mediated by proteasome β2 and β5 subunit, were not significantly affected by fangchinoline treatment.


Inhibition on Proteasome β1 Subunit Might Contribute to the Anti-Cancer Effects of Fangchinoline in Human Prostate Cancer Cells.

Li D, Lu Y, Sun P, Feng LX, Liu M, Hu LH, Wu WY, Jiang BH, Yang M, Qu XB, Guo DA, Liu X - PLoS ONE (2015)

Inhibitive effects of fangchinoline on cell proliferation and cellular proteasome activities of PC-3 cells and LnCap cells.(A) Cell viability (MTT assay result) of PC-3 cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. Data were statistical results of three independent experiments. (B) Cellular proteasome activities of PC-3 cells treated with 0.1% DMSO or fangchinoline at different concentrations for 24 h. (C) Cell viability (MTT assay result) of LnCap cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. (D) Cellular proteasome activities of control PC-3 cells treated with 0.1% DMSO (solvent control) or fangchinoline at different concentrations for 24 h. Data were statistical results of three independent experiments. *p<0.05 vs. solvent control. Carfilzomib was used as positive control.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4626104&req=5

pone.0141681.g002: Inhibitive effects of fangchinoline on cell proliferation and cellular proteasome activities of PC-3 cells and LnCap cells.(A) Cell viability (MTT assay result) of PC-3 cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. Data were statistical results of three independent experiments. (B) Cellular proteasome activities of PC-3 cells treated with 0.1% DMSO or fangchinoline at different concentrations for 24 h. (C) Cell viability (MTT assay result) of LnCap cells treated with various concentrations of fangchinoline for 24, 48 or 72 h. (D) Cellular proteasome activities of control PC-3 cells treated with 0.1% DMSO (solvent control) or fangchinoline at different concentrations for 24 h. Data were statistical results of three independent experiments. *p<0.05 vs. solvent control. Carfilzomib was used as positive control.
Mentions: As shown in Fig 2A, fangchinoline could dose-dependently and time-dependently decrease the viability of PC-3 cells. The IC50 values of fangchinoline in inhibiting cell proliferation of PC-3 cells were 27.53±3.346 μM for 24 h, 13.13±1.579 μM for 48 h, and 7.247±0.3122 μM for 72 h treatment, respectively. Furthermore, as shown in Fig 2B, fangchinoline could dose-dependently inhibit the C-L activity of cellular proteasome, which was mediated by proteasome β1 subunit. The inhibition on C-L activity was significant at doses of 1 and 10 μM fangchinoline. The activities of proteasome trypsin-like (T-L) and chymotrypsin-like (CT-L) activities, mediated by proteasome β2 and β5 subunit, were not significantly affected by fangchinoline treatment.

Bottom Line: Moore.Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline.Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit.

View Article: PubMed Central - PubMed

Affiliation: Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, P.R. China; Changchun University of Chinese Medicine, Changchun 130117, P.R. China.

ABSTRACT
Fangchinoline is a bisbenzylisoquinoline alkaloid isolated from Radix Stephaniae tetrandrae S. Moore. Fangchinoline and its structure analogue, tetrandrine, exhibited direct binding affinity with recombinant human proteasome β1 subunit and also inhibited its activity in vitro. In cultured prostate PC-3 cells and LnCap cells, fangchinoline could dose-dependently inhibit cell proliferation and caspase-like activity of cellular proteasome which was mediated by proteasome β1 subunit. The inhibitive effect of fangchinoline on caspase-like activity of proteasome was also observed in purified human erythrocyte 20S proteasome. In PC-3 cells, fangchinoline induced cell cycle arrest at G0/G1 phase and apoptosis. Treatment of PC-3 tumor-bearing nude mice with fangchinoline inhibited tumor growth, induced apoptosis and also caused decrease in proteasome activities in tumor xenografts. Dose-dependent and time-dependent accumulation of ubiquitinated proteins and important proteasome substrates such as p27, Bax and IκB-α were observed in fangchinoline-treated cells. Over-expression of proteasome β1 subunit by plasmid transfection increased sensitivity of cells to the cytotoxicity of fangchinoline while knockdown of proteasome β1 subunit ameliorated cytotoxicity of fangchinoline in PC-3 cells. Results of the present study suggested that proteasome inhibition was involved in the anti-cancer effects of fangchinoline. Fangchinoline and its structure analogues might be new natural proteasome inhibitors targeting β1 subunit.

No MeSH data available.


Related in: MedlinePlus