Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells - PubMed (original) (raw)

Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells

C Herold et al. Br J Cancer. 2002.

Free PMC article

Abstract

Efficacy of chemotherapy in advanced stages of colorectal tumours is limited. The quinolone antibiotic ciprofloxacin was recently shown to inhibit growth and to induce apoptosis in human bladder carcinomas cells. We investigated the effect of ciprofloxacin on colon carcinoma lines in vitro. CC-531, SW-403 and HT-29 colon carcinoma and HepG2 hepatoma cells (control cells) were exposed to ciprofloxacin. Proliferation was assessed by bromodeoxyuridine-incorporation into DNA and apoptosis was measured by flow cytometry after propidium iodide or JC-1 staining. Expression of anti-apoptotic Bcl-2 and pro-apoptotic Bax was analyzed by semiquantitative Western blot analysis and activity of caspases 3, 8 and 9 by substrate-cleavage assays. Ciprofloxacin suppressed DNA synthesis of all colon carcinoma cells time- and dose-dependently, whereas the hepatoma cells remained unaffected. Apoptosis reached its maximum between 200 and 500 microg ml(-1). This was accompanied by an upregulation of Bax and of the activity of caspases 3, 8 and 9, and paralleled by a decrease of the mitochondrial membrane potential. Ciprofloxacin decreases proliferation and induces apoptosis of colon carcinoma cells, possibly in part by blocking mitochondrial DNA synthesis. Therefore, qualification of ciprofloxacin as adjunctive agent for colorectal cancer should be evaluated.

Copyright 2002 The Cancer Research Campaign

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Figures

Figure 1

Figure 1

Ciprofloxacin induces morphological signs of apoptosis in colon cancer cell lines. Colon cancer cells CC-531 (A) and SW-403 (B) as well as hepatoma cells HepG2 (C) untreated (1) and after 18 h of incubation with 100 μg ml−1 (2) and 500 μg ml−1 (3) of ciprofloxacin.

Figure 2

Figure 2

Ciprofloxacin inhibits DNA-synthesis in colon carcinoma cells. DNA-synthesis was measured by BrdU-incorporation in CC-531, HT-29, SW-403 and HepG2 hepatoma cells after treatment with 100, 200 or 500 μg ml−1 ciprofloxacin (24 h). Results for untreated cells were set at 100%. Values are means±s.d. of six independent experiments.

Figure 3

Figure 3

Apoptosis is induced after 24 h of incubation with ciprofloxacin. When compared to untreated control cells (A), incubation of SW-403 cells with 500 μg ml−1 (B) for 24 h caused a decrease of S/G2-cells (M3 and M4) and an increase of sub-G1-cells (M1) M2 marks cells in G1 phase.

Figure 4

Figure 4

The Ciprofloxacin effect on apoptosis induction of colon cancer cells is time-dependent. Apoptosis rates were measured using FACS analysis. Results are given as means±s.d. of at least three independent experiments.

Figure 5

Figure 5

Ciprofloxacin induces mitochondrial injury of CC-531 (A) and HepG2 (B) cells. Green fluorescence of JC-1 dye was assessed as a parameter for mitochondrial breakdown. Increased green fluorescence is detectable in CC-531 cells incubated with 500 μg ml−1 ciprofloxacin for 48 h (dotted line) compared to cells treated with 10% FCS alone (black line) but not in HepG2 controls.

Figure 6

Figure 6

Different caspases are activated after incubation with ciprofloxacin. Activity of caspase 3, 8 and 9 was measured by a colourimetric peptide substrate-cleavage ELISA. Cells were treated with 100, 200 or 500 μg ml−1 ciprofloxacin (24 h). Basal activity of untreated cells was set at 100%. Values are means±s.d. of five independent experiments. Dotted line –––: value for untreated cells.

Figure 7

Figure 7

Ciprofloxacin increases the Bax : Bcl-2 ratio time-depently in colon cancer cells. Values of untreated cells were set to 1. Representative Western blot showing the increase of Bax and decrease of Bcl-2 expression in CC-531 and SW-403 cells.

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