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1.
Fig. 1.

Fig. 1. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Ceftriaxone inhibits EGF-induced anchorage-independent growth of JB6 P+ cells. (A) Chemical structure of ceftriaxone. (B) Ceftriaxone is not toxic to JB6 P+ cells. Cells were treated with different concentrations of ceftriaxone for 24 or 48h and cytotoxicity was measured by MTS assay. Absorbance was read at an optical density of 492nm. Data are shown as mean ± standard deviation from triplicate experiments. (C) Ceftriaxone inhibits EGF-induced anchorage-independent growth of JB6 P+ cells. Cells were cultured with different concentrations of ceftriaxone for 1 week and then colonies were counted. The magnification of representative pictures for the anchorage-independent growth assay is 25X. Data are shown as mean ± standard deviation from triplicate experiments. The asterisk (*) indicates a significant (P < 0.05) decrease in colony formation with ceftriaxone compared with the untreated control group.

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.
2.
Fig. 4.

Fig. 4. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Aurora B is highly expressed in lung cancer cell lines and ceftriaxone inhibits their anchorage-independent growth. (A) Aurora B expression levels are higher in lung cancer cell lines compared with normal lung cells. Aurora B expression level was confirmed by western blot analysis using an antibody against Aurora B. α-Tubulin was used as a loading control. Data are representative of results from triplicate experiments. (B) Ceftriaxone inhibits anchorage-independent growth of A549 cells. Cells were cultured with different concentrations of ceftriaxone for 10 days and then colonies were counted. Data are shown as mean ± standard deviation from triplicate experiments. The asterisk (*) indicates a significant (P < 0.05) decrease in colony formation with ceftriaxone compared with the untreated control group. Reversine was used as a positive control. Ceftriaxone also inhibits anchorage-independent growth of H520 (C) and H1650 (D) cells. Cells were cultured with different concentrations of ceftriaxone for 7 days (H520) or 14 days (H1650) and then colonies were counted. The magnification of representative photographs for the anchorage-independent growth assay is 25X. Data are shown as mean ± standard deviation from triplicate experiments. The asterisk (*) indicates a significant (P < 0.05) decrease in colony formation with ceftriaxone compared with the untreated control group. Reversine was used as a positive control.

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.
3.
Fig. 5.

Fig. 5. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Aurora B is required for the inhibitory effects of ceftriaxone. (A) Ceftriaxone inhibits Aurora B activity in A549 cells. A549 cells were treated with different concentrations of ceftriaxone for 2h. Cells were then harvested and total ERKs, RSK, Aurora B, histone H3 and phosphorylated ERKs, RSK, Aurora B and histone H3 proteins were detected by western blotting using specific antibodies. Data are representative of results from triplicate experiments. (B) Expression level of Aurora B in A549 cells is decreased by knockdown of Aurora B. A549 cells were transiently transfected with sh-mock or sh-Aurora B and cell lysates were analyzed by western blot. (C) Ceftriaxone has less effect on anchorage-independent cell growth of sh-Aurora B-transfected cells than that of sh-mock cells. A549 cells were grown in soft agar with ceftriaxone (0, 200, 500, 1000 µM) for 10 days and colonies were counted. Data are represented as mean ± standard deviation from triplicate experiments. The asterisk (*) indicates a significant decrease compared with sh-mock cells (P < 0.05).

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.
4.
Fig. 2.

Fig. 2. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Ceftriaxone specifically binds with Aurora B in vitro and ex vivo. (A) Proposed binding mode of ceftriaxone and Aurora B. Ceftriaxone is shown in stick representation and surrounded by a semitransparent surface, which occupies the ATP-binding site between the N and C terminals. (B) Interaction between ceftriaxone and Aurora B. Ceftriaxone forms hydrogen bonds with ALA173 and LYS101 and maintains van der Waals contacts with the side chain of PHE172. Carbons of ceftriaxone are colored magenta, whereas oxygen, nitrogen and sulfur are shown in red, blue and yellow, respectively. The in vitro ATP competitive binding (C) and ex vivo binding (D) of ceftriaxone with Aurora B were confirmed using a pull-down assay. A recombinant human Aurora B protein (200ng) or A549 cell lysates (500 µg) were incubated with ceftriaxone-Sepharose 4B (or Sepharose 4B only as control) beads. Proteins bounded to the beads were boiled and resolved by 10% SDS-PAGE followed by western blot analysis. Data shown are representative of triplicate experiments.

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.
5.
Fig. 6.

Fig. 6. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Ceftriaxone suppresses tumor growth by inhibiting Aurora B activity in vivo. (A) Ceftriaxone treatment suppresses tumor volume compared with the vehicle-treated group. Tumor volume was measured and recorded as described in section ‘Materials and methods’. The asterisk (*) indicates a significant increased tumor size (P < 0.05) in the vehicle-treated group compared with the ceftriaxone-treated group as determined by one-way analysis of variance. (B) Ceftriaxone has no effect on the body weight of mice. The body weight of each mouse was measured and recorded once a week. Data are shown as mean ± satndard error. (C) Ceftriaxone inhibits expression of phosphorylated histone H3 in vivo. Immunohistochemistry analysis was used to determine the level of phosphorylated histone H3 in tumor tissues. Top, representative photos from each group; phosphorylated histone H3 is indicated by arrows. Bottom, percentage of phosphorylated histone H3 expression with ceftriaxone treatment compared with the vehicle group. The magnification of representative photos for the immunohistochemistry staining is ×100. Data are shown as mean ± standard deviation from triplicate experiments. The asterisks (**) indicate a significant (P < 0.01) decrease in phosphorylated histone H3 expression in the100mg/kg ceftriaxone-treated group compared with the vehicle-treated group. The duration of this animal study was 57 days. It was terminated when most untreated tumors reached 1 cubic centimeter per University of Minnesota IACUC guidelines.

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.
6.
Fig. 3.

Fig. 3. From: Ceftriaxone, an FDA-approved cephalosporin antibiotic, suppresses lung cancer growth by targeting Aurora B.

Ceftriaxone suppresses Aurora B activity in vitro and in cells. (A) Ceftriaxone inhibits Aurora B activity in vitro. The inhibitory effect of ceftriaxone on Aurora B was determined by an in vitro kinase assay as described in section ‘Materials and methods’. The expression level of phosphorylated histone H3 (Ser10; arrow) was confirmed by western blot analysis using an antibody against phosphorylated histone H3. Total histone-H3 was used as a loading control. Data are representative of results from triplicate experiments. (B) Ceftriaxone inhibits Aurora B activity in JB6 P+ cells. Different concentrations of ceftriaxone were incubated with JB6 P+ cells for 2h and cells were then treated with 10ng/ml EGF for 30min. Cells were harvested and total ERKs, RSK, Aurora B, histone H3 and phosphorylated ERKs, RSK, p38, JNKs, Aurora B and histone H3 proteins were detected by western blotting using specific antibodies. Data are representative of results from triplicate experiments. (C) Expression level of Aurora B in JB6 P+ cells is decreased by knockdown of Aurora B. JB6 P+ cells were transiently transfected with sh-mock or sh-Aurora B and cell lysates were analyzed by western blotting. (D) Ceftriaxone has less effect on anchorage-independent cell growth of sh-Aurora B cells than that of sh-mock cells. JB6 P+ cells were grown in soft agar with ceftriaxone (0, 200, 500, 1000 µM) for 7 days and colonies were counted. Data are represented as mean ± standard deviation from triplicate experiments. The asterisk (*) indicates a significant decrease compared with sh-mock cells (P < 0.05).

Xiang Li, et al. Carcinogenesis. 2012 December;33(12):2548-2557.

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