Levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1

Abstract

One cost-effective way for identifying novel cancer therapeutics is in the repositioning of available drugs for which current therapies are inadequate. Levofloxacin prevents DNA duplication in bacteria by inhibiting the activity of DNA helicase. As eukaryotic cells have similar intracellular biologic characteristics as prokaryotic cells, we speculate that antibiotics inhibiting DNA duplication in bacteria may also affect the survival of cancer cells.Here we report that levofloxacin significantly inhibited the proliferation and clone formation of cancer cells and xenograft tumor growth through cell cycle arrest at G2/M and by enhancing apoptosis. Levofloxacin significantly altered gene expression in a direction favoring anticancer activity. THBS1 and LAPTM5 were dose-dependently upregulated whereas SRD5A3, MFAP5 and P4HA1 were downregulated. Pathway analysis revealed that levofloxacin significantly regulated canonical oncogenic pathways. Specific network enrichment included a MAPK/ apoptosis/cytokine-cytokine receptor interaction pathway network that associates with cell growth, differentiation, cell death, angiogenesis and development and repair processes and a bladder cancer/P53 signaling pathway network mediating the inhibition of angiogenesis and metastasis. THBS1 overlapped in 16 of the 22 enriched apoptotic pathways and the 2 pathways in the bladder cancer/P53 signaling pathway network. P4HA1 enriched in 7 of the top 10 molecular functions regulated by differential downregulated genes. Our results indicate that levofloxacin has broad-spectrum anticancer activity with the potential to benefit cancer patients already treated or requiring prophylaxis for an infectious syndrome. The efficacy we find with levofloxacin may provide insight into the discovery and the design of novel less toxic anticancer drugs. Anti-Cancer Drugs 33: e235-e246

Combination of levofloxacin and cisplatin enhances anticancer efficacy via co-regulation of eight cancer-associated genes

“…They were dissolved or diluted by PBS before use (stored in shadow at 4℃ fridge). In our study [ 13 ], LH show strong anticancer activity at the concentrations of 25–400 µg/ml in vitro. If LH is used for treatment of malignant ascites or pleural fluid by intraperitoneal perfusion or by thoracic perfusion, LH concentration in ascites or pleural fluid will be much higher than 200 µg/ml when it is used at the standard recommended dose (500 mg/day).…”

“…Levofloxacin hydrochloride (LH) shows universal antiproliferation activity in all cancer cell lines in our previous study (Fig. S1A) [ 13 ]. The combination cytotoxicity of LH + DDP was evaluated in eight human cancer cell lines (HepG2, A549, XWLC05, SGC7901, HCT116, CNE2, U251 and MCF7).…”

“…F BW throughout the study. Data are mean ± SD from 6 mice [ 13 ]. Compared with NS group: * p < 0.05 …”

“…Several previous studies revealed the improvement of treatment efficacies of chemotherapeutic drugs by the addition of antibiotics in the patients with advanced cancer [ 20 – 23 ]. In our previous study [ 13 ], we show levofloxacin exerts broad-spectrum anticancer activity via regulation of THBS1, LAPTM5, SRD5A3, MFAP5 and P4HA1. In the present study, we first found that levofloxacin could enhance the cytotoxicity of cisplatin in all cancer cell lines in a concentration-dependent manner.…”

“…Mondal et al reported that some fluoroquinolones have antiproliferative activity and induced apoptosis in lung cancer cell line NCI-H460 in culture [ 12 ]. We reveal that levofloxacin has broad-spectrum anticancer activity in vitro and in vivo [ 13 ], in which, levofloxacin arrests cell cycle at G2/M phase, promotes apoptosis, and concentration-dependently regulates genes and signaling pathways favoring anticancer activity. Cisplatin (DDP) is a platinum-based DNA damaging agent, which is widely used in cancer chemotherapy.…”