Amphipathic Peptide-Based Fusion Peptides and Immunoconjugates for the Targeted Ablation of Prostate Cancer Cells

Abstract

We describe the design, generation, and in vitro evaluation of targeted amphipathic fusion peptides and immunoconjugates for the ablation of prostate cancer cells. The overexpression of the prostate-specific membrane antigen (PSMA) was exploited as means to specifically deliver cytotoxic peptides to prostate cancer cells. Cationic amphipathic lytic peptides were chosen as cytotoxic agents due to their ability to depolarize mitochondrial membranes and induce apoptosis. Specific delivery of the lytic peptide was facilitated by PSMA-targeting peptides and antibodies. Our results indicate that although the use of PSMA-targeted peptides only modestly enhanced the cytotoxic activity of the lytic peptide, peptide-antibody conjugates were two orders of magnitude more potent than untargeted peptide. In addition to quantifying the cytotoxic activities of the individual constructs, we also investigated the mechanisms of cell death induced by the fusion peptides and immunoconjugates. Although fusion peptides induced oncotic/necrotic death in cells, treatment with immunoconjugates resulted in apoptotic death. In summary, immunoconjugates based on lytic peptides are a promising class of therapeutics for prostate cancer therapy and warrant further investigation. [Cancer Res 2007;67(13):6368-75]

Targeted nanoparticle enhanced proapoptotic peptide as potential therapy for glioblastoma

“…We made use of this unique ability of CGKRK to reach the mitochondria by using the amphiphilic proapoptotic peptide D [KLAKLAK] 2 as the payload. D [KLAKLAK] 2 has been shown to act on mitochondria, the target of CGKRK (10), and several reports have described the antitumor activities of D [KLAKLAK] 2 (and some other peptides with similar activities), when selectively delivered to a target tissue (11)(12)(13)(14)(15)(27)(28)(29). The main limitation of these treatments has been that the D [KLA-KLAK] 2 peptide is highly toxic at the doses required for tumor treatment even with specific targeting.…”

“…However, when internalized into eukaryotic cells, D [KLAKLAK] 2 disrupts the mitochondrial membrane, which is similar to bacteria membranes, and initiates apoptotic cell death (10). Conjugating D [KLAKLAK] 2 with homing peptides has produced compounds that specifically accumulate at the homing target, causing cell death (11)(12)(13)(14)(15) 2 , however, is a highly toxic compound, even when specifically targeted to tumors (11,13). Administering toxic drugs in a nanoparticle formulation can reduce toxicity.…”

Bax-derived membrane-active peptides act as potent and direct inducers of apoptosis in cancer cells

“…Membrane-active peptides acting on the MOM (i.e. able to induce cytochrome c release and apoptosis) represent yet another type of promising, but so far unexploited, candidates in the cancer research field (Chen et al, 2001;Ellerby et al, 1999;Foillard et al, 2008;Law et al, 2006;Mai et al, 2001;Marks et al, 2005;Rege et al, 2007). Such a strategy has some parallel with the development of antibiotics from natural antimicrobial peptides (Marr et al, 2006), and in fact the use of these latter systems as anticancer drugs has already been proposed (Ellerby et al, 1999;Mader and Hoskin, 2006;Papo and Shai, 2005).…”

“…(KLAKLAK) 2 ] can induce cell death in a variety of cell types (Chen et al, 2001;Ellerby et al, 1999;Foillard et al, 2008;Foillard et al, 2009;Law et al, 2006;Mai et al, 2001;Marks et al, 2005;Rege et al, 2007). However, the mechanisms of cell killing exerted by these antibiotic peptides are unclear, because they appear to include both necrosis, which is secondary to plasma membrane disruption (Papo et al, 2006), and apoptosis, which is induced either by upregulation of death effectors (Chen et al, 2001) or by mitochondrial membrane permeabilization (Ellerby et al, 1999;Law et al, 2006;Mai et al, 2001;Marks et al, 2005;Rege et al, 2007). Of note, the cationic peptide (KLAKLAK) 2 has been reported to have very low potency (Borgne-Sanchez et al, 2007;Ellerby et al, 1999), which precludes its use as an effective anticancer drug.…”

Chondroitin Sulfate as a Molecular Portal That Preferentially Mediates the Apoptotic Killing of Tumor Cells by Penetratin-directed Mitochondria-disrupting Peptides

“…First, we constructed three fusion peptides, PR9, PT, and PD3, by replacing the leader peptide Antp in PNC27 with the CPPs, R9, TAT (4), and DPV3 (28), respectively. We then used the leader peptide Antp and three mitochondria-disrupting peptides, KLA (29), truncated BMAP27 (B27), and BMAP28 (B28) (30,31), to construct three novel chimeric peptides, KLA-Antp (KGA), B27-Antp (BA27), and B28-Antp (BA28), respectively. After comparing the cytotoxicity and specificity of these peptides, we investigated the role of several major tumor cell surface GAGs in the cellular translocation and cytotoxicity of the Antp-directed peptides.…”