Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, has antimicrobial activity against both

Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, has antimicrobial activity against both gram-positive and gram-negative organisms. to clinical trials while resulting in only a 104-54-1 IC50 few drugs being proven effective and thereby gaining approval. More than $800 million is the estimated cost with 10C17 years required for developing a drug (1). Reverse side effects, usually caused by the drugs interaction with secondary or off targets, are the most common reasons for drug development termination, either in clinical trials or even after the drug has entered the market (2). Predicting off targets for established drugs or harnessing them for novel drug development is referred to as drug repositioning (1). The supposition of drug repositioning is that these types of drugs are probablyto enter clinical trials more quickly 104-54-1 IC50 and less expensively. Thus, interest in this strategy has been growing in importance in recent years. Several pieces of convincing evidence suggest that identifying potential off targets of 104-54-1 IC50 known drugs not only will help to avoid severe side effects but also support the possibility of optimizing these for new uses (3). For example, acetophenazine, fluphenazine and periciazine, the phenothiazine derivatives, which were usually used as antipsychotic drugs in the clinic, were further identified as androgen receptor antagonists (4). Orlistat, an FDA-approved anti-obesity drug, was found to inhibit endothelial cell proliferation 104-54-1 IC50 and angiogenesis by suppressing several new targets (5C8). As a result, this compound, as well as other orlistat-like analogues, has been proposed as a potential anticancer drug (9). Ceftriaxone, an FDA-approved third-generation cephalosporin antibiotic, is used primarily to treat community-acquired or mild-to-moderate pneumonia (10) and is also a drug of 104-54-1 IC50 choice for treatment of bacterial meningitis and gonorrhea (11,12). The bactericidal activity of ceftriaxone results from the inhibition of cell wall HDM2 synthesis and is reportedly mediated through ceftriaxones binding to penicillin-binding proteins (13). Recently, Ceftiofur, a new broad-spectrum, third-generation cephalosporin antibiotic for veterinary use, was found to significantly inhibit phosphorylation of extracellular signal-regulated kinases (ERKs), p38 and c-jun NH2-terminal kinases (JNKs) in RAW264.7 mouse macrophage cells (14). The mitogen-activated protein kinase (MAPK) signaling pathway plays a key role in the regulation of gene expression, cellular growth and survival. However, abnormal MAPK signaling leads to uncontrolled cell proliferation and resistance to both apoptosis and chemotherapy (15,16). This suggested potential antitumor activities of Ceftiofur in cancer therapy. However, the potential anticancer activities of ceftriaxone, which has a structural formula similar to Ceftiofur, have not yet been fully explored. In the current study, we found that ceftriaxone inhibited anchorage-independent growth of A549, H520 and H1650 lung cancer cells. A549 cells harbor a K-Ras mutation and are a lung adenocarcinoma cell line that exhibits primary resistance to gefitinib or erlotinib. This line has been well characterized and utilized to study a variety of molecular characteristics of human tumors. Based on this information, we chose A549 cells as the major cell model for these studies. The H520 and H1650 were used to confirm that ceftriaxone has a similar effect on other lung cancer cell lines. Ceftriaxone directly bound with Aurora B and suppressed its activity and in cells. Moreover, an animal study showed that ceftriaxone inhibited Aurora B activity to suppress tumor growth of A549 and H520 lung cancer cells implanted in nude mice. These data suggest that ceftriaxone has antitumor activities exhibited through the targeting of Aurora B and also provides new indications of ceftriaxone for lung cancer treatment. Materials and methods Reagents Ceftriaxone was purchased from the University of Minnesota Boynton Health Services Pharmacy (Minneapolis, MN). Dulbeccos modified Eagles medium, basal medium eagle and other supplements were from Life Technologies, Inc. (Carlsbad, CA). CNBr-Sepharose.