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

Aranha, Olivia; Grignon, R; Fernandes, N Freitas; McDonnell, Timothy J.; Wood, David P.; Sarkar, Fazlul H.

doi:10.3892/ijo.22.4.787

Cited by 64 publications

(77 citation statements)

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“…20,39 Importantly, the pro-apoptotic effects appear to be cancer cell-specific, as illustrated in a study showing that nontumorigenic prostate epithelial cells (MLC8891) were not affected when treated in parallel to malignant PC3 prostate cells. 19 It was suggested that CPFX could be a potential chemotherapeutic agent for treatment of a range of cancers, e.g., bladder and prostate. 19,20 We studied the induction of γH2AX, which as well as being a marker for DSBs, can also be used as an indicator of apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…16,17 In addition to this, several other studies have described cell cycle and pro-apoptotic effects in cancer cells treated with CPFX. [19][20][21][22] The main aim of the current study was to investigate the relationship between CPFX-mediated DNA damage and the induction of apoptosis in TK6 lymphoblastoid cells.…”

Section: Discussionmentioning

confidence: 99%

“…[15][16][17][18] CPFX is also known to induce G 2 M cell cycle arrest and apoptosis in a variety of cancer cell lines, without such pronounced effects in normal cells. [19][20][21][22] Interestingly,…”

Section: Introductionmentioning

confidence: 99%

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Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation

Smart

Halicka²,

Traganos³

et al. 2008

Cancer Biology & Therapy

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Drugs developed for the treatment of conditions other than neoplasia can also show promise as potential antitumor agents. The fluoroquinolone antibiotic ciprofloxacin (CPFX) is known to modulate cycle cell progression and apoptosis in cancer cells, and is thought to induce DNA double-strand breaks (DSBs) via topoisomerase II (topo II) inhibition and stabilized cleavage complex (SCC) formation. DSBs trigger Ser-139 phosphorylation of histone H2AX (γH2AX) by PI-3-like kinases including ATM; γH2AX can serve as a marker of DNA damage when measured in situ using immunocytochemistry and flow cytometry. The aim of the present study was to investigate the relationship between CPFX-mediated DNA damage and induction of apoptosis in human lymphoblastoid cells and phytohaemagglutinin (PHA)-stimulated lymphocytes (Lymphs). Treatment of TK6 cells (wild-type p53) with 100 mg/ml CPFX for 2-10 h produced no increase in γH2AX; to the contrary, its level in S phase cells was reduced at 10 h compared to controls. Nevertheless, stabilization of topo IIα, ATM Ser-1981 phosphorylation and G 2 arrest was observed in TK6 cells exposed to CPFX for ≥4 h. However, following 24 h treatment, γH2AX was dramatically increased in a sub-population of cells indicating the onset of apoptosis (confirmed by presence of activated caspase 3). CPFX had a similar lack of effect on induction of γH2AX at early time points in WTK1 and NH32 cells (devoid of functional p53) and proliferating Lymphs, however, induction of apoptosis was less pronounced than in TK6 cells. Formation of SCC and activation of ATM (but lack of γH2AX induction) indicates topo II-mediated chromatin or DNA changes in the absence of DSBs; ATM activation apparently triggers the G 2 M checkpoint leading to G 2 arrest. The subsequent induction of apoptosis appears to be facilitated by functional p53. CPFX may therefore have a potential use as a chemotherapeutic agent in the treatment of lymphoblast-derived cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation

Smart

Halicka²,

Traganos³

et al. 2008

Cancer Biology & Therapy

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“…Our group and others assessed the in vitro activity of certain quinolones against various tumour cell lines. Ciprofloxacin was found to inhibit tumour cell growth of bladder transitional cell carcinoma, colon cancer and prostate cancer cell lines at concentrations achievable with its oral administration (Zehavi-Willner and Shalit, 1992;Shalit et al, 1995;Herold et al, 2002;Aranha et al, 2003).…”

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confidence: 99%

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

et al. 2006

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Etoposide (VP-16) is a topoisomerase II (topo II) inhibitor chemotherapeutic agent. Studies indicate that VP-16 enhances proinflammatory cytokines secretion from tumour cells, including IL-8, a chemokine associated with proangiogenic effects. Fluoroquinolones inhibit topo II activity in eukaryotic cells by a mechanism different from that of VP-16. The fluoroquinolone moxifloxacin (MXF) has pronounced anti-inflammatory effects in vitro and in vivo. We studied the effects of MXF and VP-16 on purified human topo II activity and further analysed their combined activity on proliferation, apoptosis and caspase-3 activity in THP-1 and Jurkat cells. Moxifloxacin alone slightly inhibited the activity of human topo II; however, in combination with VP-16 it led to a 73% reduction in enzyme activity. VP-16 inhibited cell proliferation in a time and dose-dependent manner. The addition of moxifloxacin for 72 h to low-dose VP-16 doubled its cytotoxic effect in THP-1 and Jurkat cells (1.8-and 2.6-fold decrease in cell proliferation, respectively) (Po0.004). Moxifloxacin given alone did not induce apoptosis but enhanced VP-16-induced apoptosis in THP-1 and Jurkat cells (1.8-and two-fold increase in annexin V positive cells and caspase-3 activity, respectively) (Po0.04). VP-16 induced the release of IL-8 in a time and dose-dependent manner from THP-1 cells. Moxifloxacin completely blocked the enhanced release of IL-8 induced by 0.5 and 1 mg ml À1 VP-16, and decreased IL-8 release from cells incubated for 72 h with 3 mg ml À1 VP-16 (Po0.001). VP-16 enhanced the release of IL-1b and TNF-a from THP-1 cells, whereas the addition of MXF prevented the enhanced cytokine secretion (Po0.001). We conclude that MXF significantly enhances VP-16 cytotoxicity in tumour-derived cells while preventing VP-16-induced proinflammatory cytokine release. This unique combination may have clinical benefits and cytotoxic drug 'sparing effect' and should be further studied in vivo.

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“…This family includes some pro-(Bax, Bak, Bad) and anti-(Bcl-2, Bcl-xL) apoptotic members (reviewed in Cory et al, 2003). Enhancement of the relative ratio between the protein levels of Bax and Bcl-2 or Bcl-xL has been shown to be associated with the efficient induction of apoptosis in several cancer cell lines (Mohiuddin et al, 2001;Lebedeva et al, 2002;Aranha et al, 2003;Liu et al, 2004). JN-DSRCT-1 cells express normal levels of Bax, high levels of Bcl-xL and nearly undetectable levels of Bcl-2 (data not shown).…”

Section: Discussionmentioning

confidence: 99%

Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity

2005

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Rapamycin, a complex macrolide and potent fungicide, immunosuppressant and anticancer agent, is a highly specific inhibitor of mammalian target of rapamycin (mTOR). Rapamycin has been shown to induce G1-phase cell cycle arrest in diverse tumor cell types, and its derivatives RAD001 and CCI-779 are currently in phase I and phase II clinical trials, respectively, as anticancer agents. In this study, we show that rapamycin induced the apoptotic death of JN-DSRCT-1 cells, the only available in vitro model for Desmoplastic Small Round Cell Tumors (DSRCT), while having only minor effects on their cell cycle. Rapamycin induced apoptosis by increasing the Bax : Bcl-xL ratio as a consequence of the concomitant downregulation of Bcl-xL and upregulation of Bax, both at the post-transcriptional level. Rapamycin also downregulated the levels of EWS/WT1, the fusion protein characteristic of DSRCT. Transient transfection studies using kinase-dead and rapamycin-resistant forms of mTOR demonstrated that only the downregulation of Bcl-xL was caused by the mTOR inhibitory action of rapamycin, which prevented cap-dependent translation initiation, whereas Bax upregulation was induced by rapamycin through a mechanism independent of its mTOR inhibitory activity. Moreover, rapamycin treatment downregulated the mRNA and protein levels of the 26S p44.5 proteasome subunit, suggesting the involvement of the proteasome complex in the mechanisms of rapamycin-induced apoptosis. Treatment of JN-DSRCT-1 cells with MG-132, a proteasome specific inhibitor, also resulted in the induction of apoptosis through a similar increase in the Bax : Bcl-xL ratio specifically caused by inhibiting Bax degradation and turnover. These results suggested that rapamycin induces apoptosis by preventing the degradation of the Bax protein by the proteasome, and that this process is independent of mTOR inhibition. Furthermore, these results strongly support the introduction of the use of rapamycin as a cytotoxic agent for the treatment of DSRCT.

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

Cited by 64 publications

References 0 publications

Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation

Ciprofloxacin-induced G2 arrest and apoptosis in TK6 lymphoblastoid cells is not dependent on DNA double-strand break formation

Moxifloxacin enhances antiproliferative and apoptotic effects of etoposide but inhibits its proinflammatory effects in THP-1 and Jurkat cells

Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity

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