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

Cheng-Yi Huang,Chih-Ling Chung,Ming-Wei Lin,Jenq-Lin Yang,Shun-Ban Tai,Jih-Jung Chen,Chun-Lin Chen,Yu-Hsuan Yeh,Pei-Feng Liu

doi:10.3390/ijms222111602

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.

Highlights

Tumor metastasis is the primary cause of cancer-related morbidity and mortality [1]
We evaluated the effect of a concentration range (0–40 μM) of FQs on the viability of A549 cells (Figure 1A) and HepG2 cells (Figure S1) using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay
The results revealed that phorbol 12-myristate 13-acetate (PMA)- and TGF-β-induced migration and invasion of A549 cells were significantly suppressed in the FQ pretreatment groups compared with the controls

Summary

Introduction

Tumor metastasis is the primary cause of cancer-related morbidity and mortality [1]. New anticancer agents that prevent malignant transformation, invasion, and metastasis of cancer cells have recently attracted attention [2]. Cancer cells invade tissues at distant metastatic sites by using matrix metalloproteinases (MMPs) to degrade a variety of ECM proteins [3]. Among these MMPs, MMP-2 and MMP-9 are zinc-containing gelatinases that have been shown to induce tumor progression by promoting cell invasion and metastasis [4]. The inhibition of MMP-2 and MMP-9 activities can be employed as an important anti-metastasis strategy to prevent cancer cell dissemination These two MMPs have similar properties, their gene expression is regulated by different regulatory elements in their respective promoter regions [5]

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Results

Conclusion