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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
Author(s) -
Bourikas Leonidas A,
Kolios George,
Valatas Vassilis,
Notas George,
Drygiannakis Ioannis,
Pelagiadis Iordanis,
Manousou Pinelopi,
Klironomos Stefanos,
Mouzas Ioannis A,
Kouroumalis Elias
Publication year - 2009
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2009.00161.x
Subject(s) - apoptosis , cell culture , cell growth , transforming growth factor , biology , growth inhibition , cell cycle , secretion , cancer research , microbiology and biotechnology , pharmacology , endocrinology , biochemistry , genetics
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)‐β1‐mediated growth inhibition and its role in TGF‐β1 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‐β1 and 5‐FU on proliferation, apoptosis, necrosis and cell cycle. The effect of ciprofloxacin on TGF‐β1 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‐β1 production by HT‐29 cells and its anti‐proliferative effect was abolished when TGF‐β1 was blocked. Confirming this mechanism further, ciprofloxacin had no effect on Caco‐2, a human colonic epithelial cell line that lacks functional TGF‐β1 receptors. Conclusions and implications: We demonstrate a novel anti‐proliferative and immunoregulatory effect of ciprofloxacin on human intestinal epithelial cells mediated via TGF‐β1.