Ciprofloxacin mediated cell growth inhibition, S/G(2)-M cell cycle arrest,and apoptosis in a human transitional cell carcinoma of the bladder cell line

The second most prevalent urological malignancy in middle aged and elderly men is bladder cancer, with 90% of the cases being transitional cell carcin omas. The success of current systemic and intravesical therapeutic agents, such as cisplatin, thiotepa, Adriamycin, mitomycin C, and bacillus Calmette -Guerin, is limited with recurrence rates reduced to 17-44%, In addition, m ost of these agents require instrumentation of the urinary tract and are de livered at a significant cost and potential morbidity to the patient, Fluro quinolone antibiotics such as ciprofloxacin which can be administered p.o., may have a profound effect in bladder cancer management, This is primarily based on limited irt vitro studies on tumor cells derived from transitiona l cell carcinoma of the bladder that revealed a dose- and time-dependent in hibition of cell growth by ciprofloxacin at concentrations that are easily attainable in the urine of patients, However, the mechanism(s) by which cip rofloxacin elicits its biological effects on bladder cancer cells is not we ll documented. Our experimental data confirm previous studies showing the i n vitro cell growth inhibition of the transitional cell carcinoma of the bl adder cell line HTB9 and further showed the induction of cell cycle arrest at the S/G(2)-M checkpoints, In addition, we found down-regulation of cycli n B, cyclin E, and dephosphorylation of cdk2 in ciprofloxacin-treated bladd er tumor cells, There was also an up-regulation of Bar, which altered the B ax:Bcl-2 ratio, which may be responsible for mitochondrial depolarization r eported to be involved prior to the induction of apoptosis, The cyclin-depe ndent kinase inhibitor p21(WAF1) level was found to be decreased within 12 h of ciprofloxacin treatment and disappeared completely when HTB9 cells wer e treated with 200 mu g/ml ciprofloxacin for 24 h, The down-regulation of p 21(WAF1) closely correlated with poly(ADP-ribose) polymerase cleavage and C PP32 activation, Recent studies revealed that p21(WAF1) protects cells from apoptosis by arresting them in G(1) and further binds to pro-caspase-3, pr eventing its activation and thus, inhibiting the apoptotic cascade. Hence, the down-regulation of p21(WAF1) together with the alterations in Bar and c dk2 as observed in our studies, may define a novel mechanism by which cipro floxacin inhibits tumor cell growth and induces apoptotic tell death, The r esults of our current studies provide strong experimental evidence for the use of ciprofloxacin as a potential preventive and/or therapeutic agent for the management of transitional cell carcinoma of the bladder.