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1.
Figure 2

Figure 2. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

Taxifolin binds to EGFR and PI3-K at the ATP-binding pocket. A, taxifolin binds with EGFR in an ATP-competitive manner. B, taxifolin binds with PI3-K in an ATP-competitive manner. Active EGFR or PI3-K (200 ng) was incubated with different concentrations of ATP (0, 10 or 100 µM) and then incubated with taxifolin-conjugated Sepharose 4B beads or Sepharose 4B beads. The pulled-down proteins were analyzed by Western blot. Data are representative of three independent experiments that gave similar results. C, docking model of EGFR and taxifolin. D, docking model of PI3-K and taxifolin. Docking models show the predicted interactions.

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.
2.
Figure 1

Figure 1. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

EGFR and PI3-K are important targets of taxifolin. A, chemical structure of taxifolin. B, taxifolin binds to EGFR, PI3-K and Src in vitro. Active EGFR, PI3-K or Src (200 ng) was incubated with taxifolin-conjugated Sepharose 4B beads or Sepharose 4B beads alone, and the pulled-down proteins were analyzed by Western blot.C, taxifolin binds to EGFR and PI3-K but not to Src ex vivo. Cell lysates from JB6 P+ cells (500 µg) were incubated with taxifolin-conjugated Sepharose 4B beads or Sepharose 4B beads, and the pulled-down proteins were analyzed by Western blot. B and C, data are representative of three independent experiments that gave similar results. D, taxifolin inhibits EGFR kinase activity in vitro. Active EGFR (100 ng) was mixed with taxifolin (0, 20, 40 or 80 µM) or erlotinib (EGFR inhibitor, 10 µM) and then incubated with a [γ-32P] ATP mixture. The radioactive incorporation was determined using a scintillation counter. E, taxifolin inhibits PI3-K kinase activity in vitro. Active PI3-K (100 ng) was mixed with taxifolin (0, 20, 40 or 80 µM) or LY294002 (PI3-K inhibitor, 10 µM) and then incubated with a [γ-32P] ATP mixture. The 32P-labeled PI3P was separated by TLC and then visualized by autoradiography. D and E, data are represented as means ± S.D. from three independent experiments performed with triplicate samples and significance was determined by the Student’s t-test. The asterisk (*) indicates a significant decrease versus EGFR or PI3-K alone (P < 0.05).

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.
3.
Figure 3

Figure 3. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

Taxifolin suppresses UVB-induced phosphorylation of the EGFR and PI3-K/Akt signaling pathways. A, taxifolin has no toxicity on JB6 P+ cells. JB6 P+ cells were treated with taxifolin (0, 20, 40 or 80 µM) for 24, 48 or 72 h. Data are represented as means ± S.D. from three independent experiments performed with triplicate samples and significance was determined by the Student’s t-test. No significant difference was observed between any groups. B, taxifolin inhibits UVB-induced phosphorylation of EGFR. C, taxifolin inhibits UVB-induced phosphorylation of PI3-K/Alt signaling proteins. D, taxifolin inhibits UVB-induced phosphorylation of ERKs, p38 and JNKs. E, taxifolin inhibits UVB-induced phosphorylation of p90RSK, MSK and c-Jun. B-E, JB6 P+ cells were starved in serum-free MEM and treated with taxifolin (0, 20, 40 or 80 µM), gefitinib (2 µM) or LY294002 (2 µM) for 24 h before being exposed to UVB (4 kJ/m2). After incubation for 5 min (B), 15 min (C and D) or 30 min (E), cells were harvested and the levels of phosphorylated and total proteins were determined by Western blot. Data are representative of three independent experiments that gave similar results.

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.
4.
Figure 4

Figure 4. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

Taxifolin suppresses UVB-induced expression and promoter activity of COX-2, and PGE2 generation. A, taxifolin, as well as inhibitors of EGFR or PI3-K, suppress UVB-induced COX-2 expression. Cells were starved in serum-free MEM and then treated with taxifolin (0, 20, 40 or 80 µM), gefitinib (2 µM) and/or LY294002 (2 µM) for 24 h before being exposed to UVB (4 kJ/m2). After incubation for 4 h, the cells were harvested and the levels of COX-2 and β-actin were determined. Data are representative of three independent experiments that gave similar results. B, taxifolin suppresses the promoter activity of COX-2 induced by UVB. JB6 P+ cells stably transfected with a COX-2 luciferase reporter plasmid were starved in serum-free medium and then treated with taxifolin (0, 20, 40 or 80 µM) for 1 h before exposure to UVB (4 kJ/m2). After incubation for 12 h, luciferase activity was measured. C, taxifolin suppresses PGE2 generation induced by UVB. Cells were starved in serum-free MEM and then treated with taxifolin (0, 20, 40 or 80 µM) or celecoxib (COX-2 inhibitor, 10 µM) for 1 h before being exposed to UVB (4 kJ/m2). After incubation for 6 h, PGE2 generation in the medium was determined using a PGE2 EIA kit. D, taxifolin has no effect on COX-2 activity in vitro. In vitro COX-2 activity was determined using the COX Inhibitor Screening Assay kit.B–D, data are represented as means ± S.D. from three independent experiments performed with triplicate samples and significance was determined by the Student’s t-test. The asterisk (*) indicates a significant decrease versus UVB (B and C) or COX-2 (D) alone (P < 0.05).

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.
5.
Figure 5

Figure 5. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

The effect of taxifolin was reduced in EGFR/KO MEFs compared with EGFR/WT MEFs. A, EGFR expression is only detectable in EGFR/WT MEFs. B, the effect of taxifolin on UVB-induced phosphorylation of signaling proteins is reduced in EGFR/KO MEFs compared with EGFR/WT MEFs. EGFR/WT or KO MEFs were starved in serum-free DMEM and then treated with taxifolin (0, 40 or 80 µM) for 24 h before being exposed to UVB (4 kJ/m2). After incubation for 15 min, the cells were harvested and the levels of phosphorylated and total proteins were determined by Western blot. A and B, data are representative of 3 independent experiments that gave similar results.C, the effect of taxifolin on PGE2 generation is reduced in EGFR/KO MEFs compared with EGFR/WT MEFs. EGFR/WT or KO MEFs were starved in serum-free DMEM and then treated with taxifolin (0, 20, 40 or 80 µM) for 1 h before being exposed to UVB (4 kJ/m2). After incubation for 6 h, PGE2 generation in the medium was determined using a PGE2 EIA kit. Data are represented as means ± S.D. from three independent experiments performed with triplicate samples and significance was determined by the Student’s t-test. The asterisk (*) or (#) indicates a significant decrease versus UVB alone in EGFR/WT or KO MEFs, respectively (P < 0.05). D, taxifolin, as well as inhibitors, of EGFR, PI3-K or COX-2 suppresses EGF-induced cell transformation. JB6 P+ cells were treated with taxifolin (0, 20, 40 or 80 µM), gefitinib (0.1 µM), LY294002 (1 µM) or celecoxib (10 µM) together with 1 ng/ml EGF on solidified BME supplemented with 10% FBS and 0.5% agar. After incubation for 7 days, colonies were counted. Data are represented as means ± S.D. from three independent experiments performed with triplicate samples and significance was determined by the Student’s t-test. The asterisk (*) indicates a significant decrease versus EGF alone (P < 0.05).

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.
6.
Figure 5

Figure 5. From: Taxifolin suppresses UV-induced skin carcinogenesis by targeting EGFR and PI3-K.

Taxifolin suppresses SUV-induced skin carcinogenesis in vivo. SKH-1 hairless mice were treated as described in Materials and Methods. The mice in the vehicle group (n = 10) received topical treatment with acetone only. The mice in the 1.0 mg taxifolin group (n = 10) were treated with 1.0 mg taxifolin only. In the Veh/SUV group (n = 20), the mice were treated with acetone before SUV exposure. The mice in the 0.5 mg/SUV or 1.0 mg/SUV groups (n = 20 each) received treatment with taxifolin (0.5 or 1.0 mg, respectively) before SUV exposure. The frequency of irradiation was set at 3 times a week for 15 weeks. The respective doses of acetone or taxifolin were applied topically to the dorsal area. Tumor incidence and multiplicity were recorded weekly until the end of the experiment at week 30. A, external appearance of tumors. B, taxifolin suppresses SUV-induced tumor volume. Tumor volume was calculated according to the following formula: tumor volume (mm3) = length × width × height × 0.52. C, taxifolin suppresses SUV-induced tumor number per mouse at the end of experiment (week 30). B and C, data are represented as means ± S.E. and differences were determined by one-way ANOVA. The asterisk (*) indicates a significant decrease versus the Veh/SUV group (P < 0.01). D, taxifolin inhibits SUV-induced phosphorylation of EGFR and Akt, and COX-2 expression in mouse skin. The expression levels of phosphorylated and total proteins were analyzed by Western blot. E, taxifolin suppresses SUV-induced PGE2 production in mouse skin. PGE2 production was determined using a PGE2 EIA kit and the amount of PGE2 is expressed as ng/mg protein. D and E, data are represented as means ± S.D. and significance was determined by the Student’s t-test. The asterisk (*) indicates a significant decrease versus SUV alone (P < 0.05).

Naomi Oi, et al. Cancer Prev Res (Phila). 2012 September;5(9):1103-1114.

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