Titre du document / Document title

Suppression of human prostate cancer cell growth by ciprofloxacin is associated with cell cycle arrest and apoptosis

Auteur(s) / Author(s)

ARANHA Olivia ⁽¹⁾ ; GRIGNON Robert ⁽¹⁾ ; FERNANDES Neelesh ⁽¹⁾ ; MCDONNELL Timothy J. ⁽²⁾ ; WOOD David P. ⁽³⁾ ; SARKAR Fazlul H. ⁽¹⁾ ;

Affiliation(s) du ou des auteurs / Author(s) Affiliation(s)

⁽¹⁾ Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, ETATS-UNIS
⁽²⁾ Department of Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, ETATS-UNIS
⁽³⁾ Department of Urology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, ETATS-UNIS

Résumé / Abstract

For hormone resistant prostate cancer (HRPC), chemotherapy is used but the mortality is 100% with a mean survival time of 7-8 months. Our previous studies have shown the chemotherapeutic effect of ciprofloxacin in bladder cancer. At doses 50-400 μg/ml ciprofloxacin, the concentrations that are normally achieved at doses currently used for the treatment of anti-bacterial infections, inhibited bladder cancer cell growth and induced S/G2M arrest with modulation of key cell cycle regulatory genes and ultimately activated apoptotic processes. In this study, we investigated the effect of ciprofloxacin on androgen independent prostate carcinoma, PC3 cells and compared our results with non-tumorigenic prostate epithelial cells. The main advantage of this fluroquinolone antibiotic is its relative non-toxicity as compared to current chemotherapy, which is not very effective, for the treatment of advanced hormone resistant prostate cancer. PC3 cells as well as normal prostate epithelial cells (MLC8891) were treated with 25-400 μg/ml ciprofloxacin, and cell counting was done during 3 days of treatment. The cell death was determined using DAPI staining of cell nuclei, 7AAD-staining followed by flow cytometric analysis as well as by activation of caspase-3, a member of the ICE family of enzymes involved in the apoptotic cascade. The cell lysates were analyzed by immunoblotting techniques for the expression of key genes targeted by ciprofloxacin (p21^WAF1, Bax and Bcl-2). Translocation of bax was visualized using a fluorescence staining procedure followed by laser confocal microscopic imaging. Treatment of prostate cancer cells with ciprofloxacin resulted in a dose- and time-dependent inhibition of cell growth (70-100% with 50-400 μg/ml of the drug). There was a concomitant induction of cell cycle arrest at the S and G2/M phases of the cell cycle as well as induction of apoptosis. The CDK inhibitor p21^WAF1 was down-regulated as early as 12 h following ciprofloxacin treatment (100-200 μg/ ml for 12-24 h). There was a significant increase in the Bax/Bcl-2 ratio with translocation of Bax, a pro-apoptotic protein, to mitochondria with concomitant activation of caspase 3. These results suggest the potential usefulness of the fluroquinolone, ciprofloxacin as a chemotherapeutic agent for advanced prostate cancer. The fluroquinolone ciprofloxacin showed anti-proliferative and apoptosis inducing activity on prostate cancer cells but not on non-tumorigenic prostate epithelial cells. These effects of ciprofloxacin were mediated by cell cycle arrest at S-G2/M phase of the cell cycle, Bax translocation to mitochondrial membrane and by increasing the Bax/Bcl-2 ratio in PC3 prostate cancer cells. Based on our in vitro results, further in-depth in vivo animal or human investigations are warranted.

Revue / Journal Title

International journal of oncology   ISSN 1019-6439 

Source / Source

2003, vol. 22, n^o4, pp. 787-794 [8 page(s) (article)] (35 ref.)

Langue / Language

Anglais

Editeur / Publisher

Editorial Academy of the International Journal of Oncology, Athens, GRECE  (1992) (Revue)

Mots-clés anglais / English Keywords

Male genital diseases ; Urinary system disease ; Prostate disease ; Malignant tumor ; Quinolone derivatives ; Fluoroquinolone derivatives ; Human ; In vitro ; Biological activity ; Shutdown ; Cell cycle ; Cell death ; Apoptosis ; Cell proliferation ; Inhibition ; Antibiotic ; Antineoplastic agent ; Ciprofloxacin ; Established cell line ; Prostate ; Carcinoma ;

Mots-clés français / French Keywords

Appareil génital mâle pathologie ; Appareil urinaire pathologie ; Prostate pathologie ; Tumeur maligne ; Lignée PC 3 ; Quinolone dérivé ; Fluoroquinolone dérivé ; Homme ; In vitro ; Activité biologique ; Arrêt ; Cycle cellulaire ; Mort cellulaire ; Apoptose ; Multiplication cellulaire ; Inhibition ; Antibiotique ; Anticancéreux ; Ciprofloxacine ; Lignée cellulaire établie ; Prostate ; Carcinome ;

Mots-clés espagnols / Spanish Keywords

Aparato genital macho patología ; Aparato urinario patología ; Prostata patología ; Tumor maligno ; Quinolone derivado ; Fluoroquinolone derivado ; Hombre ; In vitro ; Actividad biológica ; Parada ; Ciclo celular ; Muerte celular ; Apoptosis ; Multiplicación celular ; Inhibición ; Antibiótico ; Anticanceroso ; Ciprofloxacino ; Línea celular establecida ; Prostata ; Carcinoma ;

Mots-clés d'auteur / Author Keywords

prostate cancer ; ciprofloxacin ; cell cycle arrest ; apoptosis ;

Localisation / Location

INIST-CNRS, Cote INIST : 26333, 35400010936400.0100