Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan.
Department of Pathology, Kaohsiung Armed Forces General Hospital, Kaohsiung 80284, Taiwan.
Int J Mol Sci. 2021 Oct 27;22(21):11602. doi: 10.3390/ijms222111602.
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.
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.
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.
氟喹诺酮类（FQs）是具有多种宿主细胞和组织效应的强效抗菌药物。虽然 FQs 可以减弱癌症的侵袭和转移，但潜在的分子机制尚不清楚。基质金属蛋白酶-9（MMP-9）在肿瘤血管生成、侵袭和转移中具有功能作用，与癌症进展和预后不良相关，这表明 MMP-9 活性和转录的抑制剂是癌症治疗的主要候选药物。尽管有大量支持 MMP-9 抑制剂作为抗癌药物的临床前数据，但由于特异性低和脱靶效应，为数不多的可用实例在治疗上没有用处。我们研究了 FQs 在转化生长因子-β（TGF-β）和佛波醇 12-肉豆蔻酸 13-乙酸酯（PMA）刺激后对癌细胞中 MMP-9 产生的影响。
在 HepG2 和 A549 细胞的汇合培养物中，分别在 RNA 提取物和培养上清液中研究了 FQs（环丙沙星、左氧氟沙星、克林沙星、加替沙星和恩诺沙星）对 TGF-β 和 PMA 诱导的 MMP-9 mRNA 表达和产生的影响。FQs 特异性地以浓度和时间依赖性方式消除了 TGF-β 和 PMA 诱导的 MMP-9 水平和活性，而不影响其他 MMP 或参与上皮-间充质转化的蛋白质。此外，FQs 通过 p38 和环 AMP 信号通路抑制 TGF-β 和 PMA 诱导的细胞迁移。
总的来说，我们证明了 FQs 通过下调 MMP-9 的表达来抑制癌细胞的迁移和侵袭，并揭示了它们在癌症治疗中潜在价值的细胞机制。
