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Development of a lytic peptide derived from BH3-only proteins

View Article: PubMed Central - PubMed

ABSTRACT

Despite great advances in cancer therapy, drug resistance is a difficult hurdle to overcome that requires development of anticancer agents with novel and effective modes of action. In a number of studies, lytic peptides have shown remarkable ability to eliminate cancer cells through a different way from traditional treatments. Lytic peptides are positively charged, amphiphilic, and are efficient at binding and disrupting the negatively charged cell membrane of cancer cells. In this study, we described the anticancer properties of a lytic peptide that was developed on the basis of the alignment of amphiphilic BH3 peptides. Our results demonstrated that the positive charge and conformation constraint were favourable for efficient cancer cell elimination. Artificial BCL-2 homology 3 peptides (ABH3) exhibited effective anticancer effects against a series of cancer cell lines in vitro and in HeLa human cervical tumour xenografts in vivo. ABH3 induced cell death in an apoptosis-independent manner through the lytic properties of the peptide that caused disruption of cell membrane. Our results showed that charge tuning and conformation constraining in a lytic peptide could be applied to optimise the anticancer activity of lytic peptides. These results also suggest that ABH3 may be a promising beginning for the development of additional lytic peptides as anticancer reagents.

No MeSH data available.


ABH3 induced cell membrane destruction. (a) LDH release of HCT116 following treatment of ABH3 or ABT-737 (20 μM, 4 h); (b) PI staining of U937 cells following treatment with ABH3 and ABT-737 (10 μM, 0.5 h); (c) Scanning electron microscope image of HCT116 upon treatment with ABH3 (10 μM, 1 h), (i) control, (ii) treated by ABH3. Values are expressed as mean (±S.D.) (n=3).
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fig4: ABH3 induced cell membrane destruction. (a) LDH release of HCT116 following treatment of ABH3 or ABT-737 (20 μM, 4 h); (b) PI staining of U937 cells following treatment with ABH3 and ABT-737 (10 μM, 0.5 h); (c) Scanning electron microscope image of HCT116 upon treatment with ABH3 (10 μM, 1 h), (i) control, (ii) treated by ABH3. Values are expressed as mean (±S.D.) (n=3).

Mentions: Next, we used a lactate dehydrogenase (LDH) release assay to investigate the ability of ABH3 to disrupt cell membranes (Figure 4a). Treatment with ABH3 led to an almost complete loss of membrane integrity. In addition, quick PI staining following treatment of ABH3 also indicated a rapid cell membrane breakage (Figure 4b). Scanning electron microscope observations of the HCT116 cell membranes showed damaged membrane morphology after treatment with ABH3 for 1 h (Figure 4c). These results all demonstrated the ability of ABH3 to drastically disrupt the cell membrane and change the cell permeability.


Development of a lytic peptide derived from BH3-only proteins
ABH3 induced cell membrane destruction. (a) LDH release of HCT116 following treatment of ABH3 or ABT-737 (20 μM, 4 h); (b) PI staining of U937 cells following treatment with ABH3 and ABT-737 (10 μM, 0.5 h); (c) Scanning electron microscope image of HCT116 upon treatment with ABH3 (10 μM, 1 h), (i) control, (ii) treated by ABH3. Values are expressed as mean (±S.D.) (n=3).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4979451&req=5

fig4: ABH3 induced cell membrane destruction. (a) LDH release of HCT116 following treatment of ABH3 or ABT-737 (20 μM, 4 h); (b) PI staining of U937 cells following treatment with ABH3 and ABT-737 (10 μM, 0.5 h); (c) Scanning electron microscope image of HCT116 upon treatment with ABH3 (10 μM, 1 h), (i) control, (ii) treated by ABH3. Values are expressed as mean (±S.D.) (n=3).
Mentions: Next, we used a lactate dehydrogenase (LDH) release assay to investigate the ability of ABH3 to disrupt cell membranes (Figure 4a). Treatment with ABH3 led to an almost complete loss of membrane integrity. In addition, quick PI staining following treatment of ABH3 also indicated a rapid cell membrane breakage (Figure 4b). Scanning electron microscope observations of the HCT116 cell membranes showed damaged membrane morphology after treatment with ABH3 for 1 h (Figure 4c). These results all demonstrated the ability of ABH3 to drastically disrupt the cell membrane and change the cell permeability.

View Article: PubMed Central - PubMed

ABSTRACT

Despite great advances in cancer therapy, drug resistance is a difficult hurdle to overcome that requires development of anticancer agents with novel and effective modes of action. In a number of studies, lytic peptides have shown remarkable ability to eliminate cancer cells through a different way from traditional treatments. Lytic peptides are positively charged, amphiphilic, and are efficient at binding and disrupting the negatively charged cell membrane of cancer cells. In this study, we described the anticancer properties of a lytic peptide that was developed on the basis of the alignment of amphiphilic BH3 peptides. Our results demonstrated that the positive charge and conformation constraint were favourable for efficient cancer cell elimination. Artificial BCL-2 homology 3 peptides (ABH3) exhibited effective anticancer effects against a series of cancer cell lines in vitro and in HeLa human cervical tumour xenografts in vivo. ABH3 induced cell death in an apoptosis-independent manner through the lytic properties of the peptide that caused disruption of cell membrane. Our results showed that charge tuning and conformation constraining in a lytic peptide could be applied to optimise the anticancer activity of lytic peptides. These results also suggest that ABH3 may be a promising beginning for the development of additional lytic peptides as anticancer reagents.

No MeSH data available.