Ciprofloxacin inhibits cell growth and synergises the effect of etoposide in hormone resistant prostate cancer cells

Background and purpose: Fluoroquinolones are potent anti-microbial agents with multiple effects on host cells and tissues. Previous studies have highlighted their pro-apoptotic effect on human cancer cells and an immunoregulatory role in animal models of inflammatory bowel disease. We examined the effect of ciprofloxacin on proliferation, cell cycle and apoptosis of HT-29 cells, a human colonic epithelial cell line sensitive to transforming growth factor (TGF)-b1-mediated growth inhibition and its role in TGF-b1 production. We also examined the effect of ciprofloxacin on proliferation of HT-29 cells in combination with 5-fluorouracil (5-FU), a well-established pro-apoptotic agent. Experimental approach: Using subconfluent cultures of HT-29 and Caco-2 cells, we studied the effect of ciprofloxacin, TGF-b1 and 5-FU on proliferation, apoptosis, necrosis and cell cycle. The effect of ciprofloxacin on TGF-b1 mRNA expression and production was studied in RNA extracts and cell culture supernatants respectively, using confluent cultures. Key results: Ciprofloxacin decreased proliferation of HT-29 cells in a concentration-and time-dependent manner. This was mediated by accumulation of HT-29 cells into the S-phase but without any effect on apoptosis or necrosis. Additionally, ciprofloxacin enhanced the antiproliferative effect of 5-FU. Interestingly, ciprofloxacin was found to up-regulate TGF-b1 production by HT-29 cells and its anti-proliferative effect was abolished when TGF-b1 was blocked. Confirming this mechanism further, ciprofloxacin had no effect on Caco-2, a human colonic epithelial cell line that lacks functional TGF-b1 receptors. Conclusions and implications:We demonstrate a novel anti-proliferative and immunoregulatory effect of ciprofloxacin on human intestinal epithelial cells mediated via TGF-b1.

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“…, 1996; Aranha et al. , 2000; Kamat and Lamm, 2004), prostate (El‐Rayes et al. , 2002), osteoblast (Holtom et al.…”

Section: Discussionmentioning

confidence: 99%

Ciprofloxacin decreases survival in HT‐29 cells via the induction of TGF‐β1 secretion and enhances the anti‐proliferative effect of 5‐fluorouracil

Bourikas¹,

Kolios

Valatas³

et al. 2009

British J Pharmacology

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“…Quinolones are known for their antibacterial and antitumor activities through alteration of the normal functions of bacterial gyrase, and are found to be a topoisomerase II inhibitor in humans [9][10][11][12][13][14][15][16][17][18] . Ciprofloxacin (Figure 1), a commonly used broadspectrum fluoroquinolone antibiotic, has shown anticancer activity in several cancer cell lines 19,20 . Other fluoroquinolone derivatives such as levofloxacin and ofloxacin have also been shown to inhibit the growth of cell bladder cancer cell lines (Figure 1) 21 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Abdel‐Aziz

El‐Azab

Alanazi

et al. 2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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The potential antitumor activities of a series of 7-(4-substituted piperazin-1-yl)fluoroquinolone derivatives (1-14a,b) using ciprofloxacin and norfloxacin as scaffolds are described. These compounds exhibit potent and broad spectrum antitumor activities using 60 human cell lines in addition to the inherent antibacterial activity. Compounds 1a, 2a, 3b, 6b and 7a were found to be the most potent, while 2b, 5b, and 6a were found to have an average activity. The results of this study demonstrated that compounds 1a, 2a, 3b, 6b and 7a (mean GI 50 ; 2.63-3.09 mM) are nearly 7-fold more potent compared with the positive control 5-fluorouracil (mean GI 50 ; 22.60 mM). More interestingly, compounds 1a, 2a, 3b, 6b and 7a have an almost antitumor activity similar to gefitinib (mean GI 50 ; 3.24 mM) and are nearly 2-fold more potent compared to erlotinib (mean GI 50 ; 7.29 mM). In silico study and ADME-Tox prediction methodology were used to study the antitumor activity of the most active compounds and to identify the structural features required for antitumor activity.

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“…The screening of a small molecule library identified new compounds that induce significant LLM and cathepsin-mediated cell death in tumor cell lines (83). Combination of DNA-damaging agents with the quinolone class of antibiotics enables lower doses of DNAdamaging agents to be used with the same apoptotic capacity when combined together (84). Thus, the potential of activating the lysosomal death pathway is promising and under development for novel cancer therapeutic approaches (85).…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C-Î´ isoform mediates lysosome labilization in DNA damage-induced apoptosis

Parent

Scherer²,

Liebisch³

et al. 2011

Int J Oncol

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Abstract.A lysosomal pathway, characterized by the partial rupture or labilization of lysosomal membranes (LLM) and cathepsin release into the cytosol, is evoked during the early events of 20-S-camptothecin lactone (CPT)-induced apoptosis in human cancer cells, including human histiocytic lymphoma U-937 cells. These lysosomal events begin rapidly and simultaneously with mitochondrial permeabilization and caspase activation within 3 h after drug treatment. Recently, in a comparative proteomics analysis performed on highlyenriched lysosomal extracts, we identified proteins whose translocation to lysosomes correlated with LLM induction after CPT treatment, including protein kinase C-‰ (PKC-‰).In this study, we show that the PKC-‰ translocation to lysosomes is required for LLM, as silencing its expression with RNA interference or suppressing its activity with the inhibitor, rottlerin, prevents CPT-induced LLM. PKC-‰ translocation to lysosomes is associated with lysosomal acidic sphingomyelinase (ASM) phosphorylation and activation, which in turn leads to an increase in ceramide (CER) content in lysosomes. The accumulation of endogenous CER in lysosomes is a critical event for CPT-induced LLM as suppressing PKC-‰ or ASM activity reduces both the CPTmediated CER generation in lysosomes and CPT-induced LLM. These findings reveal a novel mechanism by which PKC-‰ mediates ASM phosphorylation/activation and CER accumulation in lysosomes in CPT-induced LLM, rapidly activating the lysosomal pathway of apoptosis after CPT treatment.

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Ciprofloxacin inhibits cell growth and synergises the effect of etoposide in hormone resistant prostate cancer cells

Cited by 28 publications

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Ciprofloxacin decreases survival in HT‐29 cells via the induction of TGF‐β1 secretion and enhances the anti‐proliferative effect of 5‐fluorouracil

Ciprofloxacin decreases survival in HT‐29 cells via the induction of TGF‐β1 secretion and enhances the anti‐proliferative effect of 5‐fluorouracil

Synthesis and potential antitumor activity of 7-(4-substituted piperazin-1-yl)-4-oxoquinolines based on ciprofloxacin and norfloxacin scaffolds: in silico studies

Protein kinase C-Î´ isoform mediates lysosome labilization in DNA damage-induced apoptosis

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