Abstract
Dermaseptin-B2 (DRS-B2) is a multifunctional cationic antimicrobial peptide (CAP) isolated from frog skin secretion. We previously reported that DRS-B2 possesses anticancer and antiangiogenic activities in vitro and in vivo. In the present study, we evaluated the antiproliferative activity of DRS-B2 on numerous tumor cell lines, its cell internalization and studies of its molecular partners as well as their influences on its structure. Confocal microscopy using ([Alexa594]-(Cys0)-DRS-B2) shows that in sensitive human tumor cells (PC3), DRS-B2 seems to accumulate rapidly at the cytoplasmic membranes and enters the cytoplasm and the nucleus, while in less sensitive tumor cells (U87MG), DRS-B2 is found packed in vesicles at the cell membrane. Furthermore FACS analysis shows that PC3 cells viability decreases after DRS-B2 treatment while U87 MG seems to be unaffected. However, "pull down" experiments performed with total protein pools from PC3 or U87MG cells and the comparison between the antiproliferative effect of DRS-B2 and its synthetic analog containing all D-amino acids suggest the absence of a stereo-selective protein receptor. Pretreatment of PC3 cells with sodium chlorate, decreases the antiproliferative activity of DRS-B2. This activity is partially restored after addition of exogenous chondroitin sulfate C (CS-C). Moreover, we demonstrate that at nanomolar concentrations CS-C potentiates the antiproliferative effect of DRS-B2. These results highlight the partial implication of glycosaminoglycans in the mechanism of antiproliferative action of DRS-B2. Structural analysis of DRS-B2 by circular dichroism in the presence of increasing concentration of CS-C shows that DRS-B2 adopts an α-helical structure. Finally, structure-activity-relationship studies suggest a key role of the W residue in position 3 of the DRS-B2 sequence for its antiproliferative activity.
Highlights
Cancer is one of the leading causes of morbidity and mortality worldwide
The in vitro antiproliferative effect of DRS-B2 was tested on human tumor cell lines of different origins such as mammary carcinomas (MDA-MB 231, MDA-MB 453, BT-474), androgendependent or independent prostatic adenocarcinomas (PC-3, DU145, LnCaP), glioblastomas (U87MG, U138MG, U373MG), pancreatic carcinomas (PANC-1, BxPC-3, MiaPaCa2) and melanomas (A375, SK-Mel-28, HT-144)
We decided to use PC3 and U87MG cell lines to study the mechanism of action of DRS-B2 on cancer cells
Summary
Cancer is one of the leading causes of morbidity and mortality worldwide. in the last decades numerous advances have been made in cancer therapy, even though present treatments do not cure more than 50% of cancer cases. The conventional chemotherapeutic agents that target cancer cells are often associated with adverse side effects observed in healthy fast-dividing cells. To evade drug resistance and reduce cytotoxicity affecting healthy cells, the development of alternative/innovative compounds with new mechanisms of action and increased selectivity for cancer cells is crucial [3]. In this context and to improve or find new therapeutic molecules against cancer, peptidelike or peptidomimetic drugs derived from either the exploration of biodiversity or from chemical synthesis became one of the new research targets. In recent years, an increasing number of articles show that these AMPs are multi-functional peptides such as anticancer agents, immuno-modulators, chemokines, vaccine adjuvants, or regulators of innate defense [4]
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