Comparison of Cytotoxic Activity in Leukemic Lineages Reveals Important Features of beta-Hairpin Antimicrobial Peptides

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Buri, Marcus V. [UNIFESP]
Vieira Torquato, Heron F. [UNIFESP]
Barros, Carlos Castilho
Ide, Jaime S.
Miranda, Antonio [UNIFESP]
Paredes-Gamero, Edgar J. [UNIFESP]
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Several reports described different modes of cell death triggered by antimicrobial peptides (AMPs) due to direct effects on membrane disruption, and more recently by apoptosis and necrosis-like patterns. Cytotoxic curves of four beta-hairpin AMPs (gomesin, protegrin, tachyplesin, and polyphemusin) were obtained from several human leukemic lineages and normal monocytes and Two cell lines were then selected based on their cytotoxic sensitivity. One was sensitive to AMPs (K562) and the other resistant (KG-1) and their effect compared between these lineages. Thus, these lineages were chosen to further investigate biological features related with their cytotoxicities to AMPs. Stimulation with AMPs produced cell death, with activation of caspase-3, in K562 lineage. Increase on the fluidity of plasmatic membrane by reducing cholesterol potentiated cytotoxicity of AMPs in both lineages. Quantification of internal and external gomesin binding to the cellular membrane of both K562 and KG-1 cells showed that more peptide is accumulated inside of K562 cells. Additionally, evaluation of multi-drug resistant pumps activity showed that KG-1 has more activity than K562 lineage. A comparison of intrinsic gene patterns showed great differences between K562 and KG-1, but stimulation with gomesin promoted few changes in gene expression patterns. Differences in internalization process through the plasma membrane, multidrug resistance pumps activity, and gene expression pattern are important features to AMPs regulated cell death. (C) 2016 Wiley Periodicals, Inc.
Journal Of Cellular Biochemistry. Hoboken, v. 118, n. 7, p. 1764-1773, 2017.