| Autor: |
Lyu Y; Department of Pharmacology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA., Kopcho S; Department of Pharmacology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA., Alvarez FA; Department of Pharmacology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA., Okeoma BC; Department of Psychiatry, Stony Brook University Hospital, Stony Brook, NY 11794, USA., Okeoma CM; Department of Pharmacology, Stony Brook University Renaissance School of Medicine, Stony Brook, NY 11794, USA. |
| Jazyk: |
angličtina |
| Zdroj: |
Cancers [Cancers (Basel)] 2020 Aug 28; Vol. 12 (9). Date of Electronic Publication: 2020 Aug 28. |
| DOI: |
10.3390/cancers12092448 |
| Abstrakt: |
BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as the drug lead because it displayed superior anti-cancer activity against both drug-resistant and drug-sensitive cancer cells, with minimal toxicity on normal cells. Probing mechanism of action using molecular dynamics simulations, biochemical and membrane biophysics studies, we observed that B18L binds BST-2 and possesses membranolytic characteristics. Furthermore, molecular biology studies show that B18L dysregulates cancer signaling pathways resulting in decreased Src and Erk1/2 phosphorylation, increased expression of pro-apoptotic Bcl2 proteins, caspase 3 cleavage products, as well as processing of the caspase substrate, poly (ADP-ribose) polymerase-1 (PARP-1), to the characteristic apoptotic fragment. These data indicate that through the coordinated regulation of membrane, mitochondrial and signaling events, B18L executes cancer cell death and thus has the potential to be developed into a potent and selective anti-cancer compound. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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