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1.
Int J Mol Sci ; 22(21)2021 Oct 20.
Article in English | MEDLINE | ID: mdl-34768734

ABSTRACT

Prostate cancer is the most common cancer in men. For patients with advanced or metastatic prostate cancer, available treatments can slow down its progression but cannot cure it. The development of innovative drugs resulting from the exploration of biodiversity could open new therapeutic alternatives. Dermaseptin-B2, a natural multifunctional antimicrobial peptide isolated from Amazonian frog skin, has been reported to possess antitumor activity. To improve its pharmacological properties and to decrease its peripheral toxicity and lethality we developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys6-LHRH to target the LHRH receptor. This hormonotoxin has a significant antiproliferative effect on the PC3 tumor cell line, with an IC50 value close to that of dermaseptin-B2. Its antitumor activity has been confirmed in vivo in a xenograft mouse model with PC3 tumors and appears to be better tolerated than dermaseptin-B2. Biophysical experiments showed that the addition of LHRH to dermaseptin-B2 did not alter its secondary structure or biological activity. The combination of different experimental approaches indicated that this hormonotoxin induces cell death by an apoptotic mechanism instead of necrosis, as observed for dermaseptin-B2. These results could explain the lower toxicity observed for this hormonotoxin compared to dermaseptin-B2 and may represent a promising targeting approach for cancer therapy.


Subject(s)
Amphibian Proteins/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Cell Line, Tumor/drug effects , Amino Acid Sequence , Amphibian Proteins/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Antimicrobial Cationic Peptides/metabolism , Antimicrobial Peptides/metabolism , Antimicrobial Peptides/pharmacology , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Cell Movement/drug effects , Cell Survival/drug effects , Gonadotropin-Releasing Hormone/analogs & derivatives , Gonadotropin-Releasing Hormone/metabolism , Gonadotropin-Releasing Hormone/pharmacology , Humans , Immunologic Factors/metabolism , Mice , Mice, Nude , Neoplasms/drug therapy , Neoplasms/metabolism , Xenograft Model Antitumor Assays
2.
PLoS One ; 12(8): e0182926, 2017.
Article in English | MEDLINE | ID: mdl-28797092

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.


Subject(s)
Amphibian Proteins/pharmacology , Antimicrobial Cationic Peptides/pharmacology , Antineoplastic Agents/pharmacology , Cell Proliferation/drug effects , Glycosaminoglycans/metabolism , Neoplasms/drug therapy , Amino Acid Sequence , Amphibian Proteins/chemistry , Animals , Antimicrobial Cationic Peptides/chemistry , Antineoplastic Agents/chemistry , Anura , Cell Line, Tumor , Humans , Neoplasms/metabolism , Structure-Activity Relationship
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