Abstract
Antimicrobial peptides (AMP) secreted by the granular glands of frog skin have been widely reported to exhibit strong bacteriostatic and bactericidal activities. Many of them have been documented with potent antiproliferative effects on multiple cancer cells, many studies also suggested that AMPs exert their functions via disrupting cell membranes. However, whether and how other cell death induction mechanism is involved in mammalian cancer cells has rarely been investigated. In this study, a novel AMP named Dermaseptin‐PS1 was isolated and identified from Phyllomedusa sauvagei, it showed strong antimicrobial activities against three types of microorganisms. In vitro antiproliferative studies on human glioblastoma U‐251 MG cells indicated that Dermaseptin‐PS1 disrupted cell membranes at the concentrations of 10−5 M and above, while the cell membrane integrity was not affected when concentrations were decreased to 10−6 M or lower. Further examinations revealed that, at the relatively low concentration (10−6 M), Dermaseptin‐PS1 induced apoptosis through mitochondrial‐related signal pathway in U‐251 MG cells. Thus, for the first time, we report a novel frog skin derived AMP with anticancer property by distinct mechanisms, which largely depends on its concentration. Together, our study provides new insights into the mechanism‐illustrated drug design and the optimisation of dose control for cancer treatment in clinic.
Highlights
Glioblastoma, as the major type of primary brain tumour, has the worst prognosis among all malignancies
In vitro antiproliferative studies on human glioblastoma U‐251 MG cells indicated that Dermaseptin‐PS1 disrupted cell membranes at the concentrations of [10−5] M and above, while the cell membrane integrity was not affected when concentrations were decreased to [10−6] M or lower
The results showed that the novel peptide Dermaseptin‐PS1 exhibited moderate antimicrobial activities against S. aureus (Figure 2A), E. coli (Figure 2B) and C. albicans (Figure 2C) with relatively low haemolytic effect (
Summary
Glioblastoma, as the major type of primary brain tumour, has the worst prognosis among all malignancies. The de novo design of AMPs from natural sources has brought much attention, as many of these peptides share the properties of being linear, cationic and α‐helical, which are essential for the initial attraction of them to the negatively charged cell membrane for consequent membrane disruption.[3] It is well established that prokaryotic The zwitterionic phospholipid, which is the main composition of eukaryotic membrane, possesses low transmembrane potential.[4,5,6,7] As a consequence, the majority of AMPs prefer to corrupt the prokaryotic membrane and eukaryotic mitochondrial membrane rather than the eukaryotic membrane Those AMPs with distinct membrane‐penetration mechanism on tumour cells that allows the receptor‐regulated internalisation, followed by induction of programmed cell death, could serve as unique and supplementary options for cancer therapy. We provide the evidence that the concentration is critical for anticancer agents to exert biological functions through differentiated mechanisms, which support the further drug design and development for targeting the intervention of mitochondrial apoptosis in cancer therapy
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