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  • Title: Role of mitochondria in ciprofloxacin induced apoptosis in bladder cancer cells.
    Author: Aranha O, Zhu L, Alhasan S, Wood DP, Kuo TH, Sarkar FH.
    Journal: J Urol; 2002 Mar; 167(3):1288-94. PubMed ID: 11832715.
    Abstract:
    PURPOSE: In our earlier series we showed that ciprofloxacin inhibits bladder tumor cell growth with concomitant S/G2M cell cycle arrest and reported an increased Bax-to-Bcl-2 ratio in cells undergoing cell death. In the current series we elucidated the molecular mechanisms by which ciprofloxacin induces apoptotic processes. MATERIALS AND METHODS: Ciprofloxacin mediated mitochondrial depolarization was detected by flow cytometry in HTB9 cells. Mitochondrial permeability transition was measured by spectrophotometry in isolated mitochondria treated with ciprofloxacin in the presence and absence of cyclosporin. The consequential decrease in mitochondrial calcium, cytochrome c release and Bax translocation to mitochondria, which resulted in the activation of caspase 3 leading to apoptotic cell death, was measured by biochemical and confocal microscopy. RESULTS: Mitochondrial depolarization was observed during ciprofloxacin induced apoptotic processes. Cyclosporin A, a known inhibitor of the mitochondrial permeability transition pore, protected cells against decreased mitochondrial potential. Also, ciprofloxacin induced an alteration of mitochondrial calcium as early as 5 minutes and this disruption of intracellular calcium homeostasis was prevented by cyclosporin. Ciprofloxacin also had a direct effect on swelling of isolated mitochondria, which was absent in the presence of cyclosporin. Mitochondrial changes were accompanied by cytochrome c release and caspase 3 activation. Our findings also showed Bcl-2 dependent subcellular redistribution of Bax to the mitochondrial membrane in ciprofloxacin treated bladder tumor cells. CONCLUSIONS: The disruption of calcium homeostasis, mitochondrial swelling and redistribution of Bax to the mitochondrial membrane are key events in the initiation of apoptotic processes in ciprofloxacin treated bladder cancer cells.
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