Fluoroquinolones Suppress TGF-β and PMA-Induced MMP-9 Production in Cancer Cells: Implications in Repurposing Quinolone Antibiotics for Cancer Treatment

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.

Mitigative Effects of Topical Norfloxacin on an Imiquimod-Induced Murine Model of Psoriasis

“…Fluoroquinolones may stop TGF-β biosynthesis by increasing the amount of endoplasmic cAMP and blocking TGF-β receptors. 179 The current trial was in agreement with Kan et al who stated that fluoroquinolones like gemifloxacin may interfere with NF-κB activation and cytokine-driven cell infiltration, as indicated by a reduced concentration of TNF-α, IL-8, and VEGF in the assessment of skin wound repair and regeneration 180 Furthermore, encouraging research signifies that gemifloxacin mitigates TNF-α-mediated NF-κB stimulation, lymphocyte penetration, and recruitment. 181 In another investigation, gemifloxacin also modified the immune response utilizing normal adult monocytes by suppressing monocytic liberation of IL-1β, IL-6, and TNF-α.…”

Mechanisms of the Antineoplastic Effects of New Fluoroquinolones in 2D and 3D Human Breast and Bladder Cancer Cell Lines

“…Cellular migration and invasion are the main features of tumor biology and play a pivotal role in metastasis, which is a major determinant of oncological patients’ death [ 61 ]. Published studies reported the anti-migratory nature of quinolone compounds in different cell lines, an effect related to their ability to inhibit metalloproteinase expression [ 28 , 33 , 62 ]. In agreement with these studies, our results highlighted that, similarly to CIP and NOR, their derivatives significantly inhibited cell migration and induced a general decrease in MMP2 and MMP9 protein levels, with better performances against MMP2 (except for MDA-MB453 cells).…”

“…In general, there seems to be consensus that reducing the zwitterionic character or increasing lipophilicity can result in a better antitumor effect [ 26 , 27 ]. Several derivatives of ciprofloxacin (CIP) and norfloxacin (NOR) have recently been shown to exhibit more potent antitumor activity than the parent compounds in various cancer cell lines [ 3 , 14 , 28 ]. In this context, our group synthesized a panel of CIP and NOR derivatives, which showed stronger antineoplastic effects in tumor cell lines of different tissue origin, also evidencing a higher extent of interaction with topoisomerase II, compared to the two precursors [ 29 ].…”

“…Effects of fluoroquinolones on migration and metastasis have also been reported. In particular, certain FQs can suppress matrix metalloproteinase 9 (MMP9) production [ 28 , 33 ].…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“…[116][117][118] For example, various proangiogenic substances, such as fibroblast growth factor (FGF), matrix metallopeptidase 9 (MMP-9), and vascular endothelial growth factor (VEGF), are produced by TAMs to promote tumor progression and metastasis in various cancers, including osteosarcoma. [119][120][121] Moreover, TAMs can also interact with various immune effector cells to induce an immunosuppressive tumor microenvironment. They can suppress the activity of T lymphocytes to facilitate tumor immune escape by overexpressing PD-1 and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptors.…”