Pseudhymenochirin-1Pb (Ps-1Pb) and pseudhymenochirin-2Pa (Ps-2Pa) are host-defense peptides, first isolated from skin secretions of the frog Pseudhymenochirus merlini (Pipidae). Ps-1Pb and Ps-2Pa are highly cytotoxic (LC50<12μM) against non-small cell lung adenocarcinoma A549 cells, breast adenocarcinoma MDA-MB-231 cells, and colorectal adenocarcinoma HT-29 cells but are also hemolytic against human erythrocytes (LC50=28±2μM for Ps-1Pb and LC50=6±1μM for Ps-2Pa). Ps-2Pa shows selective cytotoxicity for tumor cells (LC50 against non-neoplastic human umbilical vein (HUVEC) cells=68±2μM). Ps-1Pb and Ps-2Pa (5μg/mL) significantly inhibit production of the anti-inflammatory cytokine IL-10 and the multifunctional cytokine IL-6 from lipopolysaccharide (LPS)-stimulated peritoneal macrophages from C57BL/6 mice and enhance the production of the pro-inflammatory cytokine IL-23 from both unstimulated and LPS-stimulated macrophages. Ps-1Pb potently (MIC≤10μM) inhibits growth of multidrug-resistant clinical isolates of the Gram-positive bacteria methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, and the Gram-negative bacteria Acinetobacter baumannii and Stenotrophomonas maltophilia. Ps-2Pa shows the same high potency (MIC ≤ 10 μM) against the Gram-positive bacteria but is 2-4 fold less potent against the Gram-negative isolates. Ps-1Pb at 4 × MIC kills 99.9% of Escherichia coli within 30. min and 99.9% of S. aureus within 180 min. In conclusion, cytotoxicity against tumor cells, cytokine-mediated immunomodulatory properties, and broad-spectrum antimicrobial activity suggest that the Ps-1Pb and Ps-2Pa represent templates for design of non-hemolytic analogs for tumor therapy and for treatment of infections in cancer patients produced by multidrug-resistant pathogens.
Bibliographical noteFunding Information:
This work was supported by the Terry Fox Fund for Cancer Research , United Arab Emirates University , and the Ministry of Science, Belgrade, Serbia ( 175069 and 175071 ). The authors thank M. Prajeep and K. Arafat, UAE University for technical assistance, and Dr A. Sonnevend, Department of Microbiology and Immunology, UAE University for providing access to clinical isolates of bacteria.
© 2014 Elsevier B.V.
- Host-defense peptide