Ciprofloxacin decreases survival in HT-29 cells via the induction of TGF-beta1 secretion and enhances the anti-proliferative effect of 5-fluorouracil.
OBJECTIVE
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)-beta1-mediated growth inhibition and its role in TGF-beta1 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.


METHODS
Using subconfluent cultures of HT-29 and Caco-2 cells, we studied the effect of ciprofloxacin, TGF-beta1 and 5-FU on proliferation, apoptosis, necrosis and cell cycle. The effect of ciprofloxacin on TGF-beta1 mRNA expression and production was studied in RNA extracts and cell culture supernatants respectively, using confluent cultures.


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-beta1 production by HT-29 cells and its anti-proliferative effect was abolished when TGF-beta1 was blocked. Confirming this mechanism further, ciprofloxacin had no effect on Caco-2, a human colonic epithelial cell line that lacks functional TGF-beta1 receptors.


CONCLUSIONS
We demonstrate a novel anti-proliferative and immunoregulatory effect of ciprofloxacin on human intestinal epithelial cells mediated via TGF-beta1.
Department of Gastroenterology, University of Crete, Heraklion, Greece.
Leonidas A
LA
Bourikas
George
G
Kolios
Vassilis
V
Valatas
George
G
Notas
Ioannis
I
Drygiannakis
Iordanis
I
Pelagiadis
Pinelopi
P
Manousou
Stefanos
S
Klironomos
Ioannis A
IA
Mouzas
Elias
E
Kouroumalis
D000890:Anti-Infective Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002939:Ciprofloxacin / Q000494:pharmacology*; D003106:Colon / Q000166:cytology; D004357:Drug Synergism; D005472:Fluorouracil / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007413:Intestinal Mucosa / Q000166:cytology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*
D000890:Anti-Infective Agents; D000964:Antimetabolites, Antineoplastic; D007155:Immunologic Factors; D053773:Transforming Growth Factor beta1; D002939:Ciprofloxacin; D005472:Fluorouracil