The cytotoxicity and synergistic potential of aspirin and aspirin analogues towards oesophageal and colorectal cancer

Background: Oesophageal cancer (OC) is a deadly cancer because of its aggressive nature with survival rates that have barely improved in decades. Epidemiologic studies have shown that low-dose daily intake of aspirin can decrease the incidence of OC. Methods: The toxicity of aspirin and aspirin derivatives to OC and a colorectal cancer (CRC) cell line were investigated in the presence and absence of platins. Results: The data in this study show the effects of a number of aspirin analogues and aspirin on OC cell lines that originally presented as squamous cell carcinoma (SSC) and adenocarcinoma (ADC). The aspirin analogues fumaryldiaspirin (PN517) and the benzoylsalicylates (PN524, PN528 and PN529), were observed to be more toxic against the OC cell lines than aspirin. Both quantitative and qualitative apoptosis experiments reveal that these compounds largely induce apoptosis, although some necrosis was evident with PN528 and PN529. Failure to recover following the treatment with these analogues emphasized that these drugs are largely cytotoxic in nature. The OE21 (SSC) and OE33 (ADC) cell lines were more sensitive to the aspirin analogues compared to the Flo-1 cell line (ADC). A non-cancerous oesophageal primary cells NOK2101, was used to determine the specificity of the aspirin analogues and cytotoxicity assays revealed that analogues PN528 and PN529 were selectively toxic to cancer cell lines, whereas PN508, PN517 and PN524 also induced cell death in NOK2101. In combination index testing synergistic interactions of the most promising compounds, including aspirin, with cisplatin, oxaliplatin and carboplatin against the OE33 cell line and the SW480 CRC cell line were investigated. Compounds PN517 and PN524, and to a lesser extent PN528, synergised with cisplatin against OE33 cells. Cisplatin and oxaliplatin synergised with aspirin and PN517 when tested against the SW480 cell line. Conclusion: These findings indicate the potential and limitations of aspirin and aspirin analogues as chemotherapeutic agents against OC and CRC when combined with platins

High avidity drives the interaction between the streptococcal C1 phage endolysin, PlyC, with the cell surface carbohydrates of Group A Streptococcus

Endolysin enzymes from bacteriophage cause bacterial lysis by degrading the peptidoglycan cell wall. The streptococcal C1 phage endolysin PlyC, is the most potent endolysin described to date and can rapidly lyse group A, C, and E streptococci. PlyC is known to bind the Group A streptococcal cell wall, but the specific molecular target or the binding site within PlyC remain uncharacterized. Here we report for the first time, that the polyrhamnose backbone of the Group A streptococcal cell wall is the binding target of PlyC. We have also characterized the putative rhamnose binding groove of PlyC and found four key residues that were critical to either the folding or the cell wall binding action of PlyC. Based on our results, we suggest that the interaction between PlyC and the cell wall may not be a high-affinity interaction as previously proposed, but rather a high avidity one, allowing for PlyC's remarkable lytic activity. Resistance to our current antibiotics is reaching crisis levels and there is an urgent need to develop the antibacterial agents with new modes of action. A detailed understanding of this potent endolysin may facilitate future developments of PlyC as a tool against the rise of antibiotic resistance.Bio-organic Synthesi

Chemoprevention of Esophageal Adenocarcinoma

The incidence of esophageal adenocarcinoma (EAC) is rising rapidly in Western countries, and effective chemoprevention for this malignancy is lacking. Endoscopic surveillance of patients with Barrett's esophagus is currently employed to diagnose EAC at earlier stages, but this strategy has several limitations. Non-steroidal anti-inflammatory drugs and proton pump inhibitors are the most promising agents for prevention of EAC, and a randomized controlled trial of aspirin and esomeprazole is ongoing. Other agents under investigation include green tea, berries, and antioxidants. Cost-effectiveness analyses have shown that chemopreventive agents need to be highly effective at preventing EAC in order to have benefit beyond endoscopic surveillance

Barrett's Esophagus and the Increasing Role of Endoluminal Therapy

Barrett's esophagus, or the presence of specialized intestinal mucosa in the esophagus that has a malignant potential, has experienced a rapid increase in diagnosis and prevalence over the past few decades. Once thought to progress to adenocarcinoma in an orderly sequence of increasing dysplasia, recent data suggest the process can be more random. In combination with targeted surveillance endoscopy, recent improvements in technology have aided endoluminal therapy in becoming a cost-effective adjunct to medication. When used in combination, in particular, these ablative therapies have become suitable, if not preferable, alternatives to surgery in many patients