1. Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment.
- Author
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Huang CY, Yang JL, Chen JJ, Tai SB, Yeh YH, Liu PF, Lin MW, Chung CL, and Chen CL
- Subjects
- A549 Cells, Cell Line, Tumor, Cell Movement drug effects, Down-Regulation drug effects, Drug Repositioning methods, Epithelial-Mesenchymal Transition drug effects, Hep G2 Cells, Humans, Lung Neoplasms metabolism, Neoplasm Invasiveness pathology, Phosphorylcholine pharmacology, Signal Transduction drug effects, p38 Mitogen-Activated Protein Kinases metabolism, Anti-Bacterial Agents pharmacology, Fluoroquinolones pharmacology, Lung Neoplasms drug therapy, Matrix Metalloproteinase 9 metabolism, Phosphorylcholine analogs & derivatives, Polymethacrylic Acids pharmacology, Quinolones pharmacology, Transforming Growth Factor beta metabolism
- Abstract
Background: Fluoroquinolones (FQs) are potent antimicrobials with multiple effects on host cells and tissues. Although FQs can attenuate cancer invasion and metastasis, the underlying molecular mechanisms remain unclear. Matrix metalloproteinase-9 (MMP-9) has functional roles in tumor angiogenesis, invasion, and metastasis, and is associated with cancer progression and poor prognosis, suggesting that inhibitors of MMP-9 activity and transcription are prime candidates for cancer therapy. Despite numerous preclinical data supporting the use of MMP-9 inhibitors as anticancer drugs, the few available examples are not therapeutically useful due to low specificity and off-target effects. We examined the effects of FQs on MMP-9 production in cancer cells following transforming growth factor beta (TGF-β) and phorbol 12-myristate 13-acetate (PMA) stimulation., Experimental Approaches: Using confluent cultures of HepG2 and A549 cells, the effects of FQs (ciprofloxacin, levofloxacin, clinafloxacin, gatifloxacin, and enrofloxacin) on TGF-β and PMA-induced MMP-9 mRNA expression and production were studied in RNA extracts and culture supernatants, respectively. FQs specifically abrogated TGF-β and PMA-induced MMP-9 levels and activity in a concentration and time-dependent manner, without affecting other MMPs or proteins involved in epithelial-mesenchymal transition. Additionally, FQs inhibited TGF-β and PMA-induced cell migration via p38 and cyclic AMP signaling pathways., Conclusions and Implications: Overall, we demonstrated that FQs inhibit cancer cell migration and invasion by downregulating MMP-9 expression and revealed the cellular mechanisms underlying their potential value in cancer treatment.
- Published
- 2021
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