Antitumor Activity and Mechanism of Action of Hormonotoxin, an LHRH Analog Conjugated to Dermaseptin-B2, a Multifunctional Antimicrobial Peptide

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.

Enhanced Antibacterial Activity of Dermaseptin through Its Immobilization on Alginate Nanoparticles—Effects of Menthol and Lactic Acid on Its Potentialization

“…These new formulations, Alg NPs + DRS-B2 or Alg NPs + DRS-B2 + menthol or lactic acid as a therapeutic, fulfill environmental constraints and meet societal expectations. Related to environmental constraints, alginate is considered as a biodegradable and biocompatible polymer, already used for cell encapsulation [ 29 , 30 , 31 ]. Previous studies have reported the application of Alg NPs as a vector to ascertain drug delivery [ 50 ], as well as a biosensor molecule [ 51 ].…”

“…The hemolytic activities of Alg NPs (0.002 mg/mL to 2.000 mg/mL) or DRS-B2 (0.026 mg/mL to 0.208 mg/mL) or Alg NPs (0.500 mg/mL) with DRS-B2 (0.002 mg/mL to 0.208 mg/mL) were determined on fresh human erythrocytes obtained from a healthy donor, as previously described [ 30 ]. Cells treated with 0.2% Triton X100 were used as a positive control (CTL+) and correspond to the total (100%) of hemolytic activity.…”

Recent Advances in Multifunctional Antimicrobial Peptides as Immunomodulatory and Anticancer Therapy: Chromogranin A-Derived Peptides and Dermaseptins as Endogenous versus Exogenous Actors

“…Recently, a synthetic hormonotoxin molecule composed of dermaseptin-B2 associated with luteinizing hormone-releasing hormone (LHRH) was tested to improve the peptide’s antitumor activity, reducing its peripheral toxicity and lethality. This hormonotoxin displayed an anticancer effect very similar to DRS-B2 both in vitro and in vivo [ 86 ]. The LHRH addition to dermaseptin-B2 does not alter the peptide’s secondary structure and biological function [ 86 ].…”

“…This hormonotoxin displayed an anticancer effect very similar to DRS-B2 both in vitro and in vivo [ 86 ]. The LHRH addition to dermaseptin-B2 does not alter the peptide’s secondary structure and biological function [ 86 ]. On the other hand, double staining flow cytometry analysis showed that this hormonotoxin induced apoptosis instead of a necrotic process caused by DRS-B2 [ 86 ].…”

Novel Strategies in the Development of New Therapies, Drug Substances, and Drug Carriers Volume I

“…For patients with advanced and metastatic disease, the available treatment is limited to delaying the progression of the tumor. Couty et al [ 19 ] have examined a natural multifunctional antimicrobial peptide, dermaseptin-B2, that has shown some antitumor activity. To improve its pharmacological properties and decrease its peripheral toxicity and lethality, the authors have developed a hormonotoxin molecule composed of dermaseptin-B2 combined with d-Lys 6 -LHRH protein to target the luteinizing hormone-releasing hormone (LHRH) receptor.…”