Toxicological Evaluation of Occidiofungin against Mice and Human Cancer Cell Lines

Abstract

Occidiofungin, a glyco-lipopeptide obtained from the liquid culture of Burkholderia contaminans MS14, has been identified as a novel fungicide. The natural product was shown to have a minimal amount of toxicity in a previous mouse toxicity study following intraperitoneal and subcutaneous administration. In this study, the toxicity of occidiofungin was evaluated following a 5 mg/kg intravenous tail vein injection. In addition, the toxicity of occidiofungin was evaluated against human fibroblast and cancer cell lines. Weight loss was the most significant observation following intravenous administration of occidiofungin. Histology, hematology, and blood serum chemistry did not reveal any significant signs of toxicity. The activity observed in the in vitro cytotoxicity assay against the cancer cell lines was all below 75 nM concentration of occidiofungin. To date, the potency of occidiofungin against these cancer cell lines is greater than any activity observed against fungi. The findings in this study support the need to further evaluate occidiofungin's chemotherapeutic potential.

Cellular conditions that modulate the fungicidal activity of occidiofungin

“…Occidiofungin was recently shown to have activity against human tissue culture cells in in vitro toxicity assays (Hing et al . ). Comparison of normal human primary cell lines with various human cancers demonstrated significantly higher toxicity values against the cancerous lines.…”

“…; Hing et al . ). Interestingly, in vitro toxicity studies have indicated that occidiofungin targets cancer cell lines with a T 50 value that is significantly higher than that found for Candida (Hing et al .…”

A Novel Actin Binding Drug withIn VivoEfficacy

“…To date, the few actin binding antifungal compounds, including jasplakinolide (52, 53) and halichondramide (54–56), are limited by their toxicity in animals at doses that would be required to demonstrate an efficacious effect. Occidiofungin, on the other hand, is well tolerated at 5 mg/kg or 20 mg/kg when administered intravenously or subcutaneously, respectively (22, 25). This dose is much higher than the MIC of occidiofungin against several fungal pathogens.…”

“…This dose is much higher than the MIC of occidiofungin against several fungal pathogens. Furthermore, blood cells and blood chemistry following the administration of occidiofungin show no serious signs of toxicity (25). It is believed that the growth rates of the cells are attributed to the differences in killing activities.…”

“…Intravenous administration of occidiofungin to mice at a dose of 5 mg/kg was carried out with minimal induced toxicity. Blood chemistry analyses and histopathology performed on multiple organs showed a transient nonspecific stress response with no damage to organ tissues (25). Altogether, the data suggest that occidiofungin is a promising candidate for development as a clinically useful antifungal agent.…”