Development of a Cationic Amphiphilic Helical Peptidomimetic (B18L) As A Novel Anti-Cancer Drug Lead

SIMPLE SUMMARY: We have previously shown that overexpression of BST-2 in breast cancer cells promotes cancer cell adhesion and aggressiveness. Although the level of BST-2 in breast tumors is higher than those of established cancer markers, there is no therapy targeting BST-2 in cancer cells. Thus, we developed the first-generation BST-2-based peptide series―B49/B49Mod1 that impairs adhesion-dependent biological events in breast cancer cells and inhibits tumor growth. Using sequence/structure modification and bioactivity guided separation, we identified B18 as the minimal sequence required for the anti-adhesion activity of B49Mod1. The current study demonstrates that a derivative of B18, a cationic amphiphilic α-helical peptidomimetic B18L, kills drug-resistant and drug-sensitive breast cancer cells. B18L impairs cancer cell membrane and dysregulates mitochondrial and signaling events necessary for the survival of cancer cells. This study provides the first evidence that a BST-2-based peptide (B18L) is a promising therapeutic agent for treatment of breast cancers, thus supporting further development. ABSTRACT: 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.